Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses

ABSTRACT

Compounds having the following formula I: 
     
       
         
         
             
             
         
       
     
     or a stereoisomer or pharmaceutically-acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , and R 5  are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

FIELD OF THE INVENTION

This invention relates to compounds useful in the modulation of IL-12,IL-23 and/or IFNα by acting on Tyk-2 to cause signal transductioninhibition. Provided herein are amide-substituted heterocycliccompounds, compositions comprising such compounds, and methods of theiruse. The invention further pertains to pharmaceutical compositionscontaining at least one compound according to the invention that areuseful for the treatment of conditions related to the modulation ofIL-12, IL-23 and/or IFNα in a mammal.

BACKGROUND OF THE INVENTION

The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share acommon p40 subunit, are produced by activated antigen-presenting cellsand are critical in the differentiation and proliferation of Th1 andTh17 cells, two effector T cell lineages which play key roles inautoimmunity. IL-23 is composed of the p40 subunit along with a uniquep19 subunit. IL-23, acting through a heterodimeric receptor composed ofIL-23R and IL-12Rβ1, is essential for the survival and expansion of Th17cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F,IL-6 and TNF-α (McGeachy, M. J. et al., “The link between IL-23 and Th17cell-mediated immune pathologies”, Semin. Immunol., 19:372-376 (2007)).These cytokines are critical in mediating the pathobiology of a numberof autoimmune diseases, including rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, and lupus. IL-12, in addition tothe p40 subunit in common with IL-23, contains a p35 subunit and actsthrough a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2.IL-12 is essential for Th1 cell development and secretion of IFNγ, acytokine which plays a critical role in immunity by stimulating MHCexpression, class switching of B cells to IgG subclasses, and theactivation of macrophages (Gracie, J. A. et al., “Interleukin-12 inducesinterferon-gamma-dependent switching of IgG alloantibody subclass”, Eur.J. Immunol., 26:1217-1221 (1996); Schroder, K. et al.,“Interferon-gamma: an overview of signals, mechanisms and functions”, J.Leukoc. Biol., 75(2): 163-189 (2004)).

The importance of the p40-containing cytokines in autoimmunity isdemonstrated by the discovery that mice deficient in either p40, p19, orIL-23R are protected from disease in models of multiple sclerosis,rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis,among others (Kyttaris, V. C. et al., “Cutting edge: IL-23 receptordeficiency prevents the development of lupus nephritis inC57BL/6-lpr/lpr mice”, J. Immunol., 184:4605-4609 (2010); Hong, K. etal., “IL-12, independently of IFN-gamma, plays a crucial role in thepathogenesis of a murine psoriasis like skin disorder”, J. Immunol.,162:7480-7491 (1999); Hue, S. et al., “Interleukin-23 drives innate andT cell-mediated intestinal inflammation”, J. Exp. Med., 203:2473-2483(2006); Cua, D. J. et al., “Interleukin-23 rather than interleukin-12 isthe critical cytokine for autoimmune inflammation of the brain”, Nature,421:744-748 (2003); Murphy, C. A. et al., “Divergent pro- andanti-inflammatory roles for IL-23 and IL-12 in joint autoimmuneinflammation”, J. Exp. Med., 198:1951-1957 (2003)).

In human disease, high expression of p40 and p19 has been measured inpsoriatic lesions, and Th17 cells have been identified in active lesionsin the brain from MS patients and in the gut mucosa of patients withactive Crohn's disease (Lee, E. et al., “Increased expression ofinterleukin 23 p19 and p40 in lesional skin of patients with psoriasisvulgaris”, J. Exp. Med., 199:125-130 (2004); Tzartos, J. S. et al.,“Interleukin-17 production in central nervous system infiltrating Tcells and glial cells is associated with active disease in multiplesclerosis”, Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of p19,p40, and p35 in active SLE patients were also shown to be significantlyhigher compared with those in inactive SLE patients (Huang, X. et al.,“Dysregulated expression of interleukin-23 and interleukin-12 subunitsin systemic lupus erythematosus patients”, Mod. Rheumatol., 17:220-223(2007)), and T cells from lupus patients have a predominant Th1phenotype (Tucci, M. et al., “Overexpression of interleukin-12 and Thelper 1 predominance in lupus nephritis”, Clin. Exp. Immunol.,154:247-254 (2008)).

Moreover, genome-wide association studies have identified a number ofloci associated with chronic inflammatory and autoimmune diseases thatencode factors that function in the IL-23 and IL-12 pathways. Thesegenes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2,STAT3, and STAT4 (Lees, C. W. et al., “New IBD genetics: common pathwayswith other diseases”, Gut, 60:1739-1753 (2011); Tao, J. H. et al.,“Meta-analysis of TYK2 gene polymorphisms association withsusceptibility to autoimmune and inflammatory diseases”, Mol. Biol.Rep., 38:4663-4672 (2011); Cho, J. H. et al., “Recent insights into thegenetics of inflammatory bowel disease”, Gastroenterology, 140:1704-1712(2011)).

Indeed, anti-p40 treatment, which inhibits both IL-12 and IL-23, as wellas IL-23-specific anti-p19 therapies have been shown to be efficaciousin the treatment of autoimmunity in diseases including psoriasis,Crohn's Disease and psoriatic arthritis (Leonardi, C. L. et al.,“PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, ahuman interleukin-12/23 monoclonal antibody, in patients with psoriasis:76-week results from a randomized, double-blind, placebo-controlledtrial (PHOENIX 1)”, Lancet, 371:1665-1674 (2008); Sandborn, W. J. etal., “Ustekinumab Crohn's Disease Study Group. A randomized trial ofUstekinumab, a human interleukin-12/23 monoclonal antibody, in patientswith moderate-to-severe Crohn's disease”, Gastroenterology,135:1130-1141 (2008); Gottlieb, A. et al., “Ustekinumab, a humaninterleukin 12/23 monoclonal antibody, for psoriatic arthritis:randomized, double-blind, placebo-controlled, crossover trial”, Lancet,373:633-640 (2009)). Therefore, agents which inhibit the action of IL-12and IL-23 may be expected to have therapeutic benefit in humanautoimmune disorders.

The Type I group of interferons (IFNs), which include the IFNα membersas well as IFNβ, IFNε, IFNκ and IFNω, act through a heterodimer IFNα/βreceptor (IFNAR). Type I IFNs have multiple effects in both the innateand adaptive immune systems including activation of both the cellularand humoral immune responses as well as enhancing the expression andrelease of autoantigens (Hall, J. C. et al., “Type I interferons:crucial participants in disease amplification in autoimmunity”, Nat.Rev. Rheumatol., 6:40-49 (2010)).

In patients with systemic lupus erythematosus (SLE), a potentially fatalautoimmune disease, increased serum levels of interferon (IFN)α (a typeI interferon) or increased expression of type I IFN-regulated genes (aso-called IFNα signature) in peripheral blood mononuclear cells and inaffected organs has been demonstrated in a majority of patients(Bennett, L. et al., “Interferon and granulopoiesis signatures insystemic lupus erythematosus blood”, J. Exp. Med., 197:711-723 (2003);Peterson, K. S. et al., “Characterization of heterogeneity in themolecular pathogenesis of lupus nephritis from transcriptional profilesof laser-captured glomeruli”, J. Clin. Invest., 113:1722-1733 (2004)),and several studies have shown that serum IFNα levels correlate withboth disease activity and severity (Bengtsson, A. A. et al., “Activationof type I interferon system in systemic lupus erythematosus correlateswith disease activity but not with antiretroviral antibodies”, Lupus,9:664-671 (2000)). A direct role for IFNα in the pathobiology of lupusis evidenced by the observation that the administration of IFNα topatients with malignant or viral diseases can induce a lupus-likesyndrome. Moreover, the deletion of the IFNAR in lupus-prone miceprovides high protection from autoimmunity, disease severity andmortality (Santiago-Raber, M. L. et al., “Type-I interferon receptordeficiency reduces lupus-like disease in NZB mice”, J Exp. Med.,197:777-788 (2003)), and genome-wide association studies have identifiedloci associated with lupus that encode factors that function in the typeI interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y.et al., “Genetic susceptibility to systemic lupus erythematosus in thegenomic era”, Nat. Rev. Rheumatol., 6:683-692 (2010); Sandling, J. K. etal., “A candidate gene study of the type I interferon pathway implicatesIKBKE and IL8 as risk loci for SLE”, Eur. J. Hum. Genet., 19:479-484(2011)). In addition to lupus, there is evidence that aberrantactivation of type I interferon-mediated pathways are important in thepathobiology of other autoimmune diseases such as Sjögren's syndrome andscleroderma (Båve, U. et al., “Activation of the type I interferonsystem in primary Sjögren's syndrome: a possible etiopathogenicmechanism”, Arthritis Rheum., 52:1185-1195 (2005); Kim, D. et al.,“Induction of interferon-alpha by scleroderma sera containingautoantibodies to topoisomerase I: association of higherinterferon-alpha activity with lung fibrosis”, Arthritis Rheum.,58:2163-2173 (2008)). Therefore, agents which inhibit the action of typeI interferon responses may be expected to have therapeutic benefit inhuman autoimmune disorders.

Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family ofnonreceptor tyrosine kinases and has been shown to be critical inregulating the signal transduction cascade downstream of receptors forIL-12, IL-23 and type I interferons in both mice (Ishizaki, M. et al.,“Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17Axes In vivo”, J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. etal., “TYK2 kinase activity is required for functional type I interferonresponses in vivo”, PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y.et al., “Human tyrosine kinase 2 deficiency reveals its requisite rolesin multiple cytokine signals involved in innate and acquired immunity”,Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-inducedphosphorylation of members of the STAT family of transcription factors,an essential signal that leads to the dimerization of STAT proteins andthe transcription of STAT-dependent pro-inflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis,psoriasis and multiple sclerosis, demonstrating the importance ofTyk2-mediated signaling in autoimmunity and related disorders (Ishizaki,M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 andIL-23/Th17 Axes In vivo”, J. Immunol., 187:181-189 (2011); Oyamada, A.et al., “Tyrosine kinase 2 plays critical roles in the pathogenic CD4 Tcell responses for the development of experimental autoimmuneencephalomyelitis”, J. Immunol., 183:7539-7546 (2009)).

In humans, individuals expressing an inactive variant of Tyk2 areprotected from multiple sclerosis and possibly other autoimmunedisorders (Couturier, N. et al., “Tyrosine kinase 2 variant influences Tlymphocyte polarization and multiple sclerosis susceptibility”, Brain,134:693-703 (2011)). Genome-wide association studies have shown othervariants of Tyk2 to be associated with autoimmune disorders such asCrohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoidarthritis, further demonstrating the importance of Tyk2 in autoimmunity(Ellinghaus, D. et al., “Combined Analysis of Genome-wide AssociationStudies for Crohn Disease and Psoriasis Identifies Seven SharedSusceptibility Loci”, Am. J. Hum. Genet., 90:636-647 (2012); Graham, D.et al., “Association of polymorphisms across the tyrosine kinase gene,TYK2 in UK SLE families”, Rheumatology (Oxford), 46:927-930 (2007);Eyre, S. et al., “High-density genetic mapping identifies newsusceptibility loci for rheumatoid arthritis”, Nat. Genet., 44:1336-1340(2012)).

In view of the conditions that may benefit by treatment involving themodulation of cytokines and/or interferons, new compounds capable ofmodulating cytokines and/or interferons, such as IL-12, IL-23 and/orIFNα, and methods of using these compounds may provide substantialtherapeutic benefits to a wide variety of patients in need thereof.

SUMMARY OF THE INVENTION

The invention is directed to compounds of Formula I, infra, that whichare useful as modulators of IL-12, IL-23 and/or IFNα by inhibitingTyk2-mediated signal transduction.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention.

The present invention also provides a method for the modulation ofIL-12, IL-23 and/or IFNα by inhibiting Tyk-2-mediated signaltransduction comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention.

A preferred embodiment is a method for treating inflammatory andautoimmune diseases or diseases. For the purposes of this invention, aninflammatory and autoimmune disease or disorder includes any diseasehaving an inflammatory or autoimmune component.

An alternate preferred embodiment is a method for treating metabolicdiseases, including type 2 diabetes and atherosclerosis.

The present invention also provides the use of the compounds of thepresent invention for the manufacture of a medicament for the treatmentof cancers.

The present invention also provides the compounds of the presentinvention for use in therapy.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

Provided herein is at least one chemical entity chosen from compounds offormula I:

or stereoisomers, tautomers, pharmaceutically-acceptable salts,solvates, or prodrugs thereof, wherein:

Y is N or CR⁶;

R¹ is H, C₁₋₃alkyl or C₃₋₆cycloalkyl, each optionally substituted by 0-7R^(1a);

R^(1a) at each occurrence is independently hydrogen, deuterium, F, Cl,Br or CN;

R² is C₁₋₆alkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted with0-1 R^(2a) or a 5-14 membered heterocycle containing 1-4 heteroatomsselected from N, O, and S, each group substituted with 0-4 R^(2a) (forthe sake of clarity, R² is intended to include substituted methyl groupssuch as —C(O)R^(2a));

R^(2a) at each occurrence is independently hydrogen, ═O, halo, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms or 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a);

R³ is C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl or a 5-10 membered heterocyclecontaining 1-4 heteroatoms selected from N, O, and S, each groupsubstituted with 0-4 R^(3a);

R^(3a) at each occurrence is independently hydrogen, ═O, halo, OCF₃,CF₃, CHF₂, CN,

NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₂₋₆ alkenyl substituted with 0-3 R^(a), C₂₋₆ alkynyl substitutedwith 0-3 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-3 R^(a) or a —(CH₂)_(r)-5-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein said ring is selected from phenyland a heterocycle comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p), each fused ring substituted with 0-3 R^(a1);

R⁴ and R⁵ are independently hydrogen, C₁₋₄ alkyl substituted with 0-1R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or a —(CH₂)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p);

R⁶ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, OC₁₋₄haloalkyl,OC₁₋₄alkyl, CN, NO₂ or OH;

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-3 R^(d);

R^(a) and R^(a1) at each occurrence are independently hydrogen, F, Cl,Br, OCF₃, CF₃, CHF₂, CN,

NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),C₂₋₆ alkynyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p) substitutedwith 0-3 R^(f);

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(f) or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) at each occurrence is independently hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) at each occurrence is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) independently at each occurrence is hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p);

p is 0, 1, or 2; and

r is 0, 1, 2, 3, or 4.

In another embodiment are provided compounds of formula I, or astereoisomer or pharmaceutically-acceptable salt thereof, wherein R² is—C(O)R^(2a); or C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, pyrazolyl, thiazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl orpyrrolopyridinyl, each group substituted by 0-4 groups selected fromR^(2a).

In an alternate embodiment there are provided compounds of formula I, ora stereoisomer or pharmaceutically-acceptable salt thereof, wherein R²is —C(O)R^(2a); or C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl, each groupsubstituted by 0-4 groups selected from R^(2a).

In yet another embodiment there are provided compounds of formula I, ora stereoisomer or pharmaceutically-acceptable salt thereof, where R² ispyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,quinolinyl or pyrrolopyridinyl, each group substituted by 0-4 groupsselected from R^(2a).

In another embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically-acceptable salt thereof, wherein bothR⁴ and R⁵ are hydrogen.

In another embodiment, there is provided a compound of formula I,wherein

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:

R¹ is H or C₁₋₃alkyl substituted by 0-7 R^(1a);

R^(1a) at each occurrence is independently hydrogen, deuterium orhalogen (preferably H, D or F);

R² is C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, quinolinyl or pyrrolopyridinyl, each groupsubstituted by 0-4 groups selected from R^(2a);

R^(2a) at each occurrence is independently hydrogen, ═O, halo, CN,—(CH₂)_(r)OR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)NR¹¹R¹¹,—S(O)_(p)NR¹¹R¹¹, —C₁₋₆alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);

R³ is C₃₋₁₀ cycloalkyl, a C₆₋₁₀ aryl, or a 5-10 membered heterocyclecontaining 1-4 heteroatoms selected from N, O, and S, each groupsubstituted with 0-4 R^(3a);

R^(3a) at each occurrence is independently hydrogen, halo, OCF₃, CF₃,CHF₂, CN, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(C H₂)_(r)NR^(b)C(O)R^(c),—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkylsubstituted with 0-3 R^(a), C₁₋₆ haloalkyl, a —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-3 R^(a) or a —(CH₂)_(r)-5-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein that ring is selected from phenyland a 5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, S or O, each fused ring substituted by 0-3R^(a1);

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-3 R^(f) or C₃₋₁₀cycloalkyl substituted with 0-1 R^(f);

R^(a) and R^(a1) at each occurrence are independently hydrogen, ═O, F,—(CH₂)_(r)OR^(b) or C₁₋₆alkyl substituted with 0-3 R^(f);

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(f) or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f);

R^(d) at each occurrence is independently hydrogen, halo (preferably F),or —OH;

R^(f) at each occurrence is independently hydrogen, halo, CN, OH orO(C₁₋₆alkyl);

p is 0, 1 or 2; and

r is 0, 1 or 2.

In an alternate embodiment,

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein:

R¹ is H or C₁₋₃alkyl substituted by 0-7 R^(1a);

R^(1a) at each occurrence is independently hydrogen, deuterium orhalogen;

R² is —C(O)R^(2a); or C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, pyrazolyl,thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl orpyrrolopyridinyl, each group substituted by 0-4 groups selected fromR^(2a);

R^(2a) at each occurrence is independently hydrogen, ═O, halo, CN,—(CH₂)_(r)OR^(b), —(CH₂)_(r)C(O)R^(b), —NR^(b)C(O)R^(c), —C(O)OR^(b),—(CH₂)_(r)C(O)NR¹¹R¹¹, —S(O)_(p)N R¹¹R¹¹, —C₁₋₆alkyl substituted with0-3 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-2 R^(a); R³ is C₃₋₁₀ cycloalkyl, a C₆₋₁₀aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selectedfrom N, O, and S, each group substituted with 0-4 R^(3a);

R^(3a) at each occurrence is independently hydrogen, halo, OCF₃, CF₃,CHF₂, CN, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(C H₂)_(r)NR^(b)C(O)R^(c),—S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkylsubstituted with 0-3 R^(a), C₁₋₆ haloalkyl, a —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-3 R^(a) or a —(CH₂)_(r)-5-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) substituted with 0-3 R^(a);

or two R^(3a), together with the atoms to which they are attached,combine to form a fused ring wherein that ring is selected from phenyland a 5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, S or O, each fused ring substituted, asvalence allows, by 0-3 R^(a);

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-3 R^(f) or C₃₋₆cycloalkyl substituted with 0-1 R^(f);

R^(a) at each occurrence is hydrogen, ═O, F, —(CH₂)_(r)OR^(b) orC₁₋₆alkyl substituted with 0-3 R^(f);

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(f) or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl or C₃₋₆ cycloalkyl, each group substituted with 0-3R^(f);

R^(d) at each occurrence is independently hydrogen, F, Cl, Br or —OH;

R^(f) at each occurrence is independently hydrogen, halo, CN, OH orO(C₁₋₆alkyl);

p is 0, 1 or 2; and

r is 0, 1 or 2.

In another embodiment, there is provided a compound of formula I havingthe structure:

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In alternate embodiment, there is provided a compound of formula Ihaving the structure:

or a stereoisomer or pharmaceutically-acceptable salt thereof.

In another, preferred embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R² is pyrazolyl, thiazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl or quinolinyl, each group substituted with 0-3R^(2a) (especially preferred embodiments are those wherein R^(2a) ishalo, CN or phenyl).

In an alternate preferred embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R² is —C(O)R^(2a); or C₁₋₆alkyl, C₃₋₆cycloalkyl orphenyl, each group substituted with 0-3 R^(2a).

In a more preferred embodiment compounds of formula (I), or astereoisomer or pharmaceutically-acceptable salt thereof, are providedwherein R² is selected from:

In another preferred embodiment, there is provided a compound of formula(I), or a stereoisomer or pharmaceutically-acceptable salt thereof,wherein R³ is phenyl, cyclopentyl, cyclohexyl, furanyl, or pyranyl, eachsubstituted with 0-4 R^(3a) (preferably, R³ is phenyl substituted with0-3 R^(3a))

In yet another, more preferred embodiment, there is provided a compoundof formula (I), or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein:

R^(3a) at each occurrence independently is hydrogen, Ph, CN, NH₂, OCF₃,OR^(b), halo, cycloalkyl, C(O)NR¹¹R¹¹, S(O)₂NR₁₁R₁₁, C(O)R^(b),SO_(p)R^(c), NR^(b)SO_(p)R^(c), NR^(b)C(O)R, haloalkyl, CN, 5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,S or O substituted with 0-3 R^(a) and C₁₋₆ alkyl substituted with 0-3R^(a); or

one R^(3a) and a second R^(3a), together with the atoms to which theyare attached, combine to form a fused 5-7 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, S or O orphenyl;

R¹¹ at each occurrence independently is hydrogen, C₃₋₆ cycloalkylsubstituted with 0-3 R^(f), or C₁₋₄alkyl substituted with 0-1 R^(f);

R^(a) independently at each occurrence is C₁₋₆ alkyl substituted with0-3 R^(f), halo (F) or OR^(b);

R^(b) independently at each occurrence is hydrogen, 5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,S or O substituted with 0-3 R^(f), or C₁₋₆ alkyl substituted with 0-3R^(d);

R^(d) independently at each occurrence is F, Cl, Br or OH;

R^(c) independently at each occurrence is C₁₋₆ alkyl or C₃₋₆ cycloalkyl,each group substituted with 0-3 R^(f) substituted with 0-3 R^(f);

R^(f) independently at each occurrence is hydrogen, halo or OH; and

p is 2.

In another, preferred embodiment, there is provided a compound offormula (I), or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R³ is

R^(3aa) is S(O)_(p)R^(c), OR^(b), chloro, F, CN, NH₂, C(O)NR¹¹R¹¹,NR^(b)SO_(p)R^(c), NR^(b)C(O)R, C₁₋₆ alkyl substituted with 0-3 R^(a) ora 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected fromN, O, and S substituted with 0-3 R^(3a); (especially, R^(3aa) is S(O)₂Meor OMe);

R^(3ab), R^(3ac), or R^(3ad) are independently hydrogen, Cl, F, Br, CN,OR^(b), C₁₋₆ alkyl substituted 0-3 R^(a); C(O)NR¹¹R¹¹, C(O)R^(b),S(O)_(p)R^(c), or a 4-7 membered heterocycle containing 1-3 heteroatomsselected from N, O, and S substituted with 0-3 R^(a); (especiallyR^(3ab), R^(3ac), or R^(3ad) are independently, hydrogen or 5-6 memberedheterocycle containing 1-3 heteroatoms selected from N, O, and Ssubstituted with 0-2 R^(a);

R¹¹ at each occurrence independently is hydrogen, cyclopropylsubstituted with 0-3 R^(f) or C₁₋₄alkyl substituted with 0-3 R^(f);

R^(a) at each occurrence independently is C₁₋₆ alkyl substituted with0-3 R^(f), OR^(b) or halo;

R^(b) at each occurrence independently is hydrogen, C₁₋₆ alkylsubstituted with 0-2 R^(d) or a 5- to 7-membered heterocycle containing1-3 heteroatoms selected from N, O and S;

R^(c) at each occurrence independently is C₁₋₆ alkyl substituted with0-3 R^(f);

R^(d) at each occurrence independently is F or OH;

R^(f) at each occurrence independently is halo or OH; and

p is 0-2.

In an alternate preferred embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein:

R¹ is CH₃ or CD₃;

R² is —C(O)C₃₋₆ cycloalkyl substituted by 0-2 groups selected fromC₁₋₃alkyl and halo; and

R³ is

R^(3ad) wherein R^(3aa) is —O(C₁₋₃alkyl), R^(3ab) is a triazolyl ortetrazolyl group optionally substituted with C₁₋₆ alkyl substituted by0-4 groups selected from F, Cl, or Br; and R^(3ac) and R^(3ad) are bothhydrogen.

In a further alternate embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R^(3aa) is S(O)_(p)R^(c) or C(O)NR¹¹R¹¹ (morepreferably R^(3aa) is SO₂CH₃).

In a further embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically-acceptable salt thereof, whereinR^(3aa) is S(O)_(p)R^(c) or C(O)NR¹¹R¹¹ (more preferably R^(3aa) isSO₂CH₃ or C(O)NH₂).

In an alternate further embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R^(3aa) is OR^(b). More preferably R^(3aa) is OH, OMe,OCF₃, OCHF₂, OCH₂F or OEt. Even more preferably, R^(3aa) is OMe.

In a more preferred embodiment, there is provided a compound of formulaI, or a stereoisomer or pharmaceutically-acceptable salt thereof,wherein R³ is selected from:

In a more preferred embodiment, there is provided a compound of formulaI, or a stereoisomer or pharmaceutically-acceptable salt thereof,wherein R¹ is H, CH₃, C₂H₅, cyclopropyl, CD₃, or CD₂CD₃ (preferably CH₃or CD₃).

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of formula I and a pharmaceuticallyacceptable carrier or diluent.

The present invention is also directed to pharmaceutical compositionsuseful in treating diseases associated with the modulation of IL-12,IL-23 and/or IFNα by acting on Tyk-2 to cause signal transductioninhibition, comprising compounds of formula I, orpharmaceutically-acceptable salts thereof, andpharmaceutically-acceptable carriers or diluents.

The invention further relates to methods of treating diseases associatedwith the modulation of IL-12, IL-23, and/or IFNα, comprisingadministering to a patient in need of such treatment atherapeutically-effective amount of a compound according to formula I.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases (or use of thecompounds of the present invention for the manufacture of a medicamentfor the treatment of these diseases), comprising administering to a hostin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention.

The present invention also provides a method of treating an inflammatoryor autoimmune disease (or use of the compounds of the present inventionfor the manufacture of a medicament for the treatment of these diseases)comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I.

The present invention also provides a method for treating a disease (oruse of the compounds of the present invention for the manufacture of amedicament for the treatment of these diseases), comprisingadministering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thedisease is rheumatoid arthritis, multiple sclerosis, systemic lupuserythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatorybowel disease, psoriasis, Crohn's Disease, psoriatic arthritis,Sjögren's syndrome, systemic scleroderma, ulcerative colitis, Graves'disease, discoid lupus erythematosus, adult onset Stills, systemic onsetjuvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes,insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis,pancreatitis (acute or chronic), glomerulonephritis, autoimmunegastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis,pancreatitis (acute or chronic), ankylosing spondylitis, pemphigusvulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathicthrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasakidisease, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP),dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome,autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmuneinflammatory eye disease, and chronic demyelinating polyneuropathy.

The present invention also provides a method of treating an inflammatoryor autoimmune disease (or use of the compounds of the present inventionfor the manufacture of a medicament for the treatment of said diseases),comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thedisease is selected from systemic lupus erythematosus (SLE), lupusnephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenileidiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.

The present invention also provides a method for treating a rheumatoidarthritis (or use of the compounds of the present invention for themanufacture of a medicament for the treatment of rheumatoid arthritis,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I.

In addition, the present invention also provides a method of treating acondition (or use of the compounds of the present invention for themanufacture of a medicament for the treatment of these conditions)comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thecondition is selected from acute myelogenous leukemia, chronicmyelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, solid tumors, ocular neovasculization, and infantilehaemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE),rheumatoid arthritis, psoriatic arthritis, multiple vasculitides,idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergicrhinitis, multiple sclerosis (MS), transplant rejection, Type Idiabetes, membranous nephritis, inflammatory bowel disease, autoimmunehemolytic anemia, autoimmune thyroiditis, cold and warm agglutinindiseases, Evans syndrome, hemolytic uremic syndrome/thromboticthrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjögren's syndrome,peripheral neuropathies, pemphigus vulgaris and asthma.

The present invention also provides a method of treating a IL-12, IL-23,and/or IFNα mediated disease (or use of the compounds of the presentinvention for the manufacture of a medicament for the treatment of thesediseases), comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula I.

The present invention also provides a method of treating a IL-12, IL-23and/or IFNα mediated disease (or use of the compounds of the presentinvention for the manufacture of a medicament for the treatment of thesediseases), comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula I,wherein the IL-12, IL-23 and/or IFNα mediated disease is a diseasemodulated by IL-12, IL-23 and/or IFNα.

The present invention also provides a method of treating diseases,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula I incombination with other therapeutic agents.

The present invention also provides the compounds of the presentinvention for use in therapy.

In another embodiment, compounds of formula I are selected fromexemplified compounds or combinations of exemplified compounds or otherembodiments herein.

In another embodiment are compounds having an IC₅₀<1000 nM in at leastone of the assays described below.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects and/orembodiments of the invention noted herein. It is understood that any andall embodiments of the present invention may be taken in conjunctionwith any other embodiment or embodiments to describe additional morepreferred embodiments. It is also to be understood that each individualelement of the preferred embodiments is its own independent preferredembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans-geometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R³, then saidgroup may optionally be substituted with up to two R³ groups and R³ ateach occurrence is selected independently from the definition of R³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

A dash “-” that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I (e.g., an optionally substituted heteroarylgroup) refers to a moiety having 0, 1, 2, or more substituents. Forexample, “optionally substituted alkyl” encompasses both “alkyl” and“substituted alkyl” as defined below. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

As used herein, the term “at least one chemical entity” isinterchangeable with the term “a compound”.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refersto a substituted alkyl group as defined above where at least one of thesubstituents is a heteroaryl.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl orsubstituted alkyl, as defined herein. For example, the term “alkoxy”includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, andthe like. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

It should be understood that the selections for all groups, includingfor example, alkoxy, thioalkyl, and aminoalkyl, will be made by oneskilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O)then 2 hydrogens on the atom are replaced. Keto substituents are notpresent on aromatic moieties. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat when (cycloalkyl)alkyl is listed as a possible substituent, thepoint of attachment of this substituent to the core structure is in thealkyl portion. Ring double bonds, as used herein, are double bonds thatare formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and subsequentformulation into an efficacious therapeutic agent. It is preferred thatthe presently recited compounds do not contain a N-halo, S(O)₂H, orS(O)H group.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. As used herein, “carbocycle” or“carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, or7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or13-membered bicyclic or tricyclic ring, any of which may be saturated,partially unsaturated, unsaturated or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl,cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). Asshown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unlessotherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and phenyl. When the term “carbocycle” is used, it isintended to include “aryl”. A bridged ring occurs when one or morecarbon atoms link two non-adjacent carbon atoms. Preferred bridges areone or two carbon atoms. It is noted that a bridge always converts amonocyclic ring into a bicyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,and naphthyl groups, each of which may be substituted.

Accordingly, in compounds of formula I, the term “cycloalkyl” includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclooctyl, etc., as well as the following ring systems:

and the like, which optionally may be substituted at any available atomsof the ring(s). Preferred cycloalkyl groups include cyclopropyl,cyclopentyl, cyclohexyl, and

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

Thus, examples of aryl groups include:

(fluorenyl) and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom. A preferred aryl group isoptionally-substituted phenyl.

The terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”,“heterocyclic”, or “heterocyclyl” may be used interchangeably and referto substituted and unsubstituted 3-to 7-membered monocyclic groups, 7-to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups,in which at least one of the rings has at least one heteroatom (O, S orN), said heteroatom containing ring preferably having 1, 2, or 3heteroatoms selected from O, S, and N. Each ring of such a groupcontaining a heteroatom can contain one or two oxygen or sulfur atomsand/or from one to four nitrogen atoms provided that the total number ofheteroatoms in each ring is four or less, and further provided that thering contains at least one carbon atom. The nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen atoms may optionally bequaternized. The fused rings completing the bicyclic and tricyclicgroups may contain only carbon atoms and may be saturated, partiallysaturated, or fully unsaturated. The heterocyclo group may be attachedat any available nitrogen or carbon atom. As used herein the terms“heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, and“heterocyclyl” include “heteroaryl” groups, as defined below.

In addition to the heteroaryl groups described below, exemplarymonocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl,oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl. Additional monocyclicheterocyclyl groups include

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containinga heteroatom can contain one or two oxygen or sulfur atoms and/or fromone to four nitrogen atoms provided that the total number of heteroatomsin each ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. As valence allows, if said further ring is cycloalkylor heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula I, preferred heteroaryl groups include:

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) orheteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, and furyl) the reference is intended to include rings having0 to 3, preferably 0 to 2, substituents selected from those recitedabove for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, asappropriate.

The term “carbocyclyl” or “carbocyclic” refers to a saturated orunsaturated monocyclic or bicyclic ring in which all atoms of all ringsare carbon. Thus, the term includes cycloalkyl and aryl rings.Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofmono- and bicyclic carbocycles include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,phenyl and naphthyl. The carbocyclic ring may be substituted in whichcase the substituents are selected from those recited above forcycloalkyl and aryl groups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The compounds of formula I may exist in a free form (with no ionization)or can form salts which are also within the scope of this invention.Unless otherwise indicated, reference to an inventive compound isunderstood to include reference to the free form and to salts thereof.The term “salt(s)” denotes acidic and/or basic salts formed withinorganic and/or organic acids and bases. In addition, the term“salt(s)” may include zwitterions (inner salts), e.g., when a compoundof formula I, contains both a basic moiety, such as an amine or apyridine or imidazole ring, and an acidic moiety, such as a carboxylicacid. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, such as, for example, acceptable metaland amine salts in which the cation does not contribute significantly tothe toxicity or biological activity of the salt. However, other saltsmay be useful, e.g., in isolation or purification steps which may beemployed during preparation, and thus, are contemplated within the scopeof the invention. Salts of the compounds of the formula I may be formed,for example, by reacting a compound of the formula I with an amount ofacid or base, such as an equivalent amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Preferred salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically-acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples ofpharmaceutically-acceptable salts include, but are not limited to,mineral or organic acid salts of basic groups such as amines; and alkalior organic salts of acidic groups such as carboxylic acids. Thepharmaceutically-acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically-acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.Stereoisomers may include compounds which are optical isomers throughpossession of one or more chiral atoms, as well as compounds which areoptical isomers by virtue of limited rotation about one or more bonds(atropisomers). The definition of compounds according to the inventionembraces all the possible stereoisomers and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving the specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates from the conventionalmethods, such as, for example, salt formation with an optically activeacid followed by crystallization.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula I, and/or a salt and/orsolvate thereof. Any compound that will be converted in vivo to providethe bioactive agent (i.e., the compound for formula I) is a prodrugwithin the scope and spirit of the invention. For example, compoundscontaining a carboxy group can form physiologically hydrolyzable esterswhich serve as prodrugs by being hydrolyzed in the body to yield formulaI compounds per se. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood. Examples of physiologically hydrolyzableesters of compounds of formula I include C₁₋₆alkylbenzyl,4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g., acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.,methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991); and-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992), each of    which is incorporated herein by reference.

Compounds of the formula I and salts thereof may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans- andcis-isomers.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula I are also with the scope of the present invention.Methods of solvation are generally known in the art.

Utility

The compounds of the invention modulate IL-23-stimulated andIFNα-stimulated cellular functions, including gene transcription. Othertypes of cellular functions that may be modulated by the compounds ofthe instant invention include, but are not limited to, IL-12-stimulatedresponses.

Accordingly, compounds of formula I have utility in treating conditionsassociated with the modulation of the function of IL-23 or IFNα, andparticularly the selective inhibition of function of IL-23, IL-12 and/orIFNα, by acting on Tyk2 to mediate signal transduction. Such conditionsinclude IL-23-, IL-12-, or IFNα-associated diseases in which pathogenicmechanisms are mediated by these cytokines.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as modulators of IL-23-, IL-12 andIFNα-stimulated cellular responses, compounds of Formula I are useful intreating IL-23-, IL-12- or IFNα-associated diseases including, but notlimited to, inflammatory diseases such as Crohn's disease, ulcerativecolitis, asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosis, cutaneouslupus, lupus nephritis, discoid lupus erythematosus, psoriasis;auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onsetstills, systemic onset juvenile idiopathic arthritis, gout, goutyarthritis; metabolic diseases including type 2 diabetes,atherosclerosis, myocardial infarction; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,cutaneous lupus, lupus nephritis, discoid lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hyposia [should this be hypoxia], vascular hyperplasia,cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy,thrombin-induced platelet aggregation, endotoxemia and/or toxic shocksyndrome, conditions associated with prostaglandin endoperoxidasesyndase-2, and pemphigus vulgaris. Preferred methods of treatment arethose wherein the condition is selected from Crohn's disease, ulcerativecolitis, allograft rejection, rheumatoid arthritis, psoriasis,ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.Alternatively preferred methods of treatment are those wherein thecondition is selected from ischemia reperfusion injury, includingcerebral ischemia reperfusions injury arising from stroke and cardiacischemia reperfusion injury arising from myocardial infarction. Anotherpreferred method of treatment is one in which the condition is multiplemyeloma.

When the terms “IL-23-, IL-12- and/or IFNα-associated condition” or“IL-23-, IL-12- and/or IFNα-associated disease or disorder” are usedherein, each is intended to encompass all of the conditions identifiedabove as if repeated at length, as well as any other condition that isaffected by IL-23, IL-12 and/or IFNα.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula Ior a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit IL-23,IL-12 and/or IFNα function and/or treat diseases.

The methods of treating IL-23-, IL-12 and/or IFNα-associated conditionsmay comprise administering compounds of Formula I alone or incombination with each other and/or other suitable therapeutic agentsuseful in treating such conditions. Accordingly, “therapeuticallyeffective amount” is also intended to include an amount of thecombination of compounds claimed that is effective to inhibit IL-23,IL-12 and/or IFNα function and/or treat diseases associated with IL-23,IL-12 and/or IFNα.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating IL-23-, IL-12-or IFNα-associated conditions by inhibiting Tyk2-mediated signaltransduction, including IL-23-, IL-12- and/or IFNα-mediated diseases, asdescribed above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula I and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

The compounds of Formula I may be administered by any means suitable forthe condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrastemal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species that are affected by modulation of IL-23, IL-12 and/orIFNα-mediated functions.

Biological Assays Probe Displacement Assay

The probe displacement assay is conducted as follows: In a 385 wellplate, test compounds along with recombinantly expressed His-taggedprotein corresponding to amino acids 575-869 of human Tyk2 (sequenceshown below) at 2.5 nM, 40 nM((R)—N-(1-(3-(8-methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-([³H]methylsulfonyl)benzamide)(preparation described below) and 80 μg/mL Copper His-Tag scintillationproximity assay beads (Perkin Elmer, Catalog # RPNQ0095) in 50 mM HEPES,pH 7.5, containing 100 μg/mL bovine serum albumin and 5% DMSO wereincubated for 30 minutes at room temperature. The amount of radiolabeledprobe (preparation described below) bound to Tyk2 was then quantified byscintillation counting, and the inhibition by the test compoundcalculated by comparison to wells either with no inhibitor (0%inhibition) or without Tyk2 (100% inhibition). The IC₅₀ value is definedas the concentration of test compound required to inhibit radiolabeledprobe binding by 50%.

Protein Sequence of recombinant Hig-tagged Tyk2 (575-869):

MGSSHHHHHH SSGETVRFQG HMNLSQLSFH RVDQKEITQL SHLGQGTRTN VYEGRLRVEG SGDPEEGKMDDEDPLVPGRD RGQELRVVLKVLDPSHHDIA LAFYETASLM SQVSHTHLAF VHGVCVRGPE NIMVTEYVEHGPLDVWLRRE RGHVPMAWKM VVAQQLASAL SYLENKNLVHGNVCGRNILL ARLGLAEGTS PFIKLSDPGVGLGALSREER VERIPWLAPE CLPGGANSLS TAMDKWGFGA TLLEICFDGE APLQSRSPSEKEHFYQRQHRLPEPSCPQLA TLTSQCLTYE PTQRPSFRTI LRDLT RL.

The preparation of radiolabeled probe,(R)—N-(1-(3-(8-methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-([³H]methylsulfonyl)benzamide,was performed as described below.

2-([³H]Methylsulfonyl)benzoic acid: 2-Mercaptobenzoic acid (2.3 mg,0.015 mmol) and cesium carbonate (2 mg, 0.006 mmol) were added to a 5 mLround-bottomed flask. The flask was attached to a ported glass vacuumline and anhydrous DMF (0.5 mL) was introduced with magnetic stirring.An ampoule of tritiated methyl iodide (200 mCi, Perkin-Elmer lot3643419) was added to the reaction flask and stirring was maintained atrt for 3 h. In-process HPLC analysis with radiometric detectionindicated 80% conversion to the desired product by comparison withauthentic standard. Without purification, the crude product was reactedwith mCPBA (10 mg, 0.058 mmol) pre-dissolved in CH₂Cl₂ (1 mL) at roomtemperature with stirring. The reaction was stirred for 7 h andadditional mCPBA (10 mg, 0.058 mmol) was added. The reaction was stirredfor approximately 24 h and HPLC analysis indicated 35-40% conversion tothe desired sulfonate product. The crude product was purified bysemi-preparative HPLC (Luna 5 m C18 (10×250 cm); A: MeOH/H₂O=15/85 (0.1%TFA); B: MeOH; 270 nm; 0-8 min 0% B 1 ml/min; 8-10 min 0% B 1-3 ml/min;10-55 min 0% B 3 ml/min; 55-65 min 0-10% B 3 ml/min; 65-75 min 10-50% B3 ml/min; 75-80 min 50-100% B 3 ml/min) to give 81 mCi (40%radiochemical yield) of 2-([³H]methylsulfonyl)benzoic acid productidentified by its HPLC co-elution with an authentic standard. Theradiochemical purity was measured by HPLC to be 99% (Luna 5μ C18(4.6×150 cm); A: H₂O (0.1% TFA); B: MeOH; 1.2 ml/min; 270 nm; 0-10 min20% B; 10-15 min 20-100% B; 15-25 min 100% B. The product was dissolvedin anhydrous acetonitrile to give a final solution activity of 5.8mCi/mL.

(R)—N-(1-(3-(8-Methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-([³H]methylsulfonyl)benzamide:A solution of 2-([³H]methylsulfonyl)benzoic acid (23.2 mCi) inacetonitrile was added to a 5 mL round-bottomed flask which was thenattached to a vacuum line and carefully evaporated to dryness.(R)-2-(3-(1-Aminoethyl)phenyl)-N,8-dimethyl-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-5-amine(prepared as described in WO 2004/106293 and Dyckman et al., Bioorganicand Medicinal Chemistry Letters, 383-386 (2011)) (1.1 mg, 0.0033 mmol)and PyBOP (2 mg, 0.0053 mmol) dissolved in anhydrous DMF (1.5 mL) wereadded to the flask followed by N,N-diisopropylethylamine (0.010 mL). Theresulting clear solution was stirred at room temperature for 18 h. HPLCanalysis (Luna 5. C18 (4.6×150 cm); A: H₂O (0.1% TFA); B: MeOH; 1.2ml/min; 335 nm; 0-20 min 50% B; 20-25 min 50-100% B; 25-30 min 100% B)indicated approximately a 20% conversion to the desired product byretention time comparison to a sample of non-radiolabeled(R)—N-(1-(3-(8-methyl-5-(methylamino)-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-(methylsulfonyl)benzamide.The crude reaction mixture was purified by semi-preparative HPLC (Luna5μ C18 (10×250 cm); A: MeOH/H₂O=50/50 (0.1% TFA); B: MeOH; 335 nm; 0-40min 0% B 3 ml/min; 40-45 min 0-100% B 3 ml/min). The purificationroutine was performed a second time to yield a total of 1.7 mCi (7%radiochemical yield) of the desired product in 99.9% radiochemicalpurity. Mass spectral analysis of the tritiated product (m/z M+H 527.33)was used to establish the specific activity at 80.6 Ci/mmol.

Probe Displacement Data Example Probe Displacement No. (EC₅₀, μM) 4 0.135 0.41 10 0.10 16 6.57E−03 51 7.19E−03 52 5.13E−03 61 1.66E−03 676.53E−03 69 0.07 70 5.22E−03 73 5.21E−03 75 6.18E−03 76 6.17E−03 841.28E−03 85 7.36E−03 87 2.02E−03 94 1.72E−03 102 1.59E−03 108 1.46E−03112 1.94E−03 114 1.89E−03 125 0.11 134 5.64E−03 140 0.07 142 6.95E−03146 1.70E−03 147 8.77E−04 151 7.22E−03 154 0.09 155 7.13E−03 160 0.07176 6.35E−03 181 6.97E−03 183 5.72E−03 186 0.06 188 5.10E−03 194 0.08

Kit225 T Cell Assay

Kit225 T cells with a stably-integrated STAT-dependent luciferasereporter were plated in RPMI (Gibco) containing 10% heat-inactivated FBS(Gibco) and 100 U/mL PenStrep (Gibco). The cells were then stimulatedwith either 20 ng/mL human recombinant IL-23 or 200 U/mL humanrecombinant IFNα (PBL InterferonSource) for 5-6 hours. Luciferaseexpression was measured using the STEADY-GLO® Luciferase Assay System(Promega) according to the manufacturer's instructions. Inhibition datawere calculated by comparison to no inhibitor control wells for 0%inhibition and non-stimulated control wells for 100% inhibition. Doseresponse curves were generated to determine the concentration requiredto inhibit 50% of cellular response (IC₅₀) as derived by non-linearregression analysis.

Kit225 T Cell Inhibition Data Example IL-23 Kit225 Reporter IFNα Kit225Reporter No. (IC₅₀, nM) (IC₅₀, nM) 1 0.03 0.02 2 0.14 0.05 3 0.10 0.06 42.30 1.15 5 12.50 6.36 6 0.19 0.11 7 0.07 0.05 8 0.13 0.09 9 0.06 0.0910 0.16 0.40 11 0.10 0.06 12 0.23 0.10 13 0.02 0.05 14 0.01 0.01 15 0.040.05 16 0.04 0.02 17 0.57 0.36 18 0.10 0.03 19 0.09 0.09 20 0.02 0.02 210.08 0.06 22 0.16 0.10 23 0.10 0.04 24 0.06 0.05 25 0.14 0.08 26 0.060.05 27 0.01 0.02 28 0.42 0.61 29 0.14 0.08 30 0.02 0.01 31 0.08 0.09 320.07 0.05 33 0.66 0.40 34 0.19 0.17 35 0.21 0.04 36 0.11 0.03 37 0.540.08 38 0.17 0.10 39 0.34 0.13 40 0.08 0.12 41 0.16 0.19 42 0.15 0.26 430.46 0.07 44 0.25 0.10 45 0.42 0.31 46 0.20 0.06 47 0.05 0.02 48 0.330.11 49 0.56 0.22 50 0.31 0.49 51 0.04 0.02 52 0.01 9.21E−03 54 0.040.02 55 0.02 0.02 56 7.01E−03 5.45E−03 57 6.01E−03 6.48E−03 58 0.028.59E−03 59 0.02 0.02 60 0.01 3.38E−03 61 0.02 8.37E−03 62 0.03 0.02 630.04 0.06 64 0.25 0.06 65 0.06 0.02 66 0.02 0.03 67 0.10 0.07 686.56E−03 3.45E−03 69 0.38 0.16 70 0.02 0.02 71 0.01 5.99E−03 72 0.130.04 73 0.08 0.05 74 0.02 5.15E−03 75 0.07 0.04 76 1.99E−03 3.49E−03 770.07 0.02 78 0.32 0.07 79 0.08 0.03 80 0.38 0.19 81 0.24 0.10 82 0.110.06 83 0.05 0.04 84 0.02 9.39E−03 85 0.17 0.05 86 0.03 0.02 87 0.024.10E−03 88 0.02 9.97E−03 89 0.02 2.18E−03 90 0.54 0.39 91 0.02 3.62E−0392 0.04 8.63E−03 93 0.05 0.01 94 0.03 8.59E−03 95 0.10 0.02 96 0.047.38E−03 97 0.01 0.02 98 0.03 9.16E−03 99 0.06 0.02 100 0.04 0.05 1010.10 0.06 102 0.04 0.03 103 0.02 6.06E−03 104 0.19 0.04 105 0.18 0.14106 0.08 0.08 107 0.09 0.14 108 8.49E−03 3.54E−03 109 0.01 7.13E−03 1100.08 0.02 111 0.03 0.01 112 7.49E−03 3.72E−03 113 0.03 4.41E−03 1148.29E−03 3.77E−03 115 2.96E−03 1.60E−03 116 0.02 0.03 117 0.08 0.03 1180.03 0.02 119 0.01 7.37E−03 120 0.06 0.01 121 2.64E−03 2.33E−03 122 0.033.20E−03 123 5.90E−03 6.81E−03 124 0.70 0.49 125 0.17 0.43 126 0.04 0.03127 0.03 0.02 128 6.08E−03 3.17E−03 129 0.02 0.01 130 9.70E−03 0.01 1310.02 0.02 132 0.02 0.02 133 8.03E−03 3.81E−03 134 0.03 0.01 135 3.83E−031.40E−03 136 0.02 6.04E−03 137 0.01 6.92E−03 138 0.03 0.03 139 0.21 0.15140 0.32 0.33 141 0.04 0.02 142 6.59E−03 4.30E−03 143 0.04 0.14 144 0.013.15E−03 145 0.01 8.44E−03 146 0.01 5.33E−03 147 1.01E−03 4.42E−03 1480.02 0.01 149 0.17 0.05 150 0.02 0.01 151 0.02 0.02 152 0.13 0.03 1530.15 0.03 154 0.59 0.43 155 0.03 0.03 156 0.04 0.01 157 0.23 0.15 1580.01 0.02 159 0.11 0.08 160 0.41 0.31 161 0.21 0.21 162 0.12 0.06 1630.04 0.03 164 0.30 0.17 165 0.34 0.23 166 0.27 0.21 167 0.31 0.33 1680.10 0.08 169 0.04 0.03 170 0.23 0.39 171 0.05 0.13 172 5.45E−036.19E−03 173 0.12 0.02 174 0.02 6.97E−03 175 0.02 0.01 176 0.04 0.02 1771.52E−03 1.63E−03 178 0.03 0.01 179 0.45 0.14 180 0.06 0.02 181 0.040.02 182 0.19 0.08 183 0.03 3.67E−03 184 6.41E−03 7.20E−03 185 0.28 0.12186 0.17 0.08 187 0.05 188 0.12 0.05 189 0.15 0.03 190 0.02 0.02 1910.01 8.63E−03 192 0.04 0.03 193 0.03 0.04 194 0.63 0.41 195 0.01 0.02196 0.07 0.16 197 0.29 0.26 198 5.22E−03 5.67E−03 199 0.19 0.23 200 0.080.03 201 0.02 4.13E−03 202 0.29 0.33 203 0.31 0.11 204 0.07 0.02 2050.14 0.05 206 4.38E−03 7.12E−04

Methods of Preparation

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry.General synthetic schemes for preparing compounds of the presentinvention are described below. These schemes are illustrative and arenot meant to limit the possible techniques one skilled in the art mayuse to prepare the compounds disclosed herein. Different methods toprepare the compounds of the present invention will be evident to thoseskilled in the art. Additionally, the various steps in the synthesis maybe performed in an alternate sequence in order to give the desiredcompound or compounds. Examples of compounds of the present inventionprepared by methods described in the general schemes are given in thepreparations and examples section set out hereinafter.

Scheme 1 illustrates the preparation of title compounds of the invention(I) from the intermediate pyridazine (II) or 1,2,4-triazine (III) alongwith an amine (IV). The coupling of the halo-pyridazine may be affectedby many of the ways known to achieve displacement of 6-halo-pyridazinesby amines. This includes, but is not limited to, the palladium catalyzedN-arylation of amines, and nucleophilic displacement of the halide bythe amine. A variety of palladium sources can be used to affect thecoupling including both palladium(II) salts (for example palladiumdiacetate) as well as neutral palladium (such as tetrakistriphenylphosphine palladium or tris(dibenzylideneacetone)dipalladium).A large number of catalyst ligands are suitable for this transformationincluding bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(BrettPhos) and many others that those versed in synthetic chemistry arefamiliar with (see Surry, D. S. et al., Chem. Sci., 2:27-50 (2011)). Avariety of bases can be employed (such as potassium carbonate, sodiumtert-butoxide, cesium carbonate and the like) as well as a number ofsolvents (such as 1,4-dioxane, toluene and dimethylacetamide and thelike). Nucleophilic displacement is generally possible at elevatedtemperatures (typically >100° C.) in the presence or absence of eitheran acid or base catalyst. Heating can be accomplished using either amicrowave or conventional heating. Amines are most typically, but notexclusively, aliphatic in such displacements. In the case of thesulfide/sulfoxide triazine (III) the displacement is best accomplishedusing nucleophilic displacement under thermal conditions, due to theincreased electrophilicity of this position this is possible both forthe electron rich aliphatic amines as well as the more electron pooranilines and related.

Scheme 2 illustrates the preparation of the amides II/III from thecorresponding carboxylic acids (V/VI) by coupling with an amine (VII).This coupling may be affected by many of the ways known to preparecarboxamides. For example, condensation of acid with amine (VII) may beeffected by treatment of the carboxylic acid with an activating reagent,such as a water-soluble carbodiimide (EDC), in the presence of anN-hydroxy triazole (HOAt or HOBt, or the like) and amine (VII) in thepresence of base (preferably triethylamine, diisopropylethylamine, orthe like) in an appropriate polar aprotic solvent(N,N-dimethylformamide, acetonitrile, dichloromethane, or the like).Alternative combination reagents, reagents that combine an activatingreagent and a hydroxy triazole, such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or(benxotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) can be used in the presence of a base. The carboxylic acid mayalso be converted to an acid chloride by treatment with an appropriatechlorinating agent (thionyl chloride, oxalyl chloride, or the like).Similarly, the carboxylic acid may be converted to an acyl fluoride uponexposure to a fluorinating agent (such as cyanuric fluoride).Condensation of the acyl halide (chloride or fluoride) with the amine(VII) (typically carried out in the presence of a base such as pyridineor triethylamine in an aprotic solvent) may then provide the amideII/III.

Scheme 3 illustrates the preparation of acids V/VI via saponification ofester VIII/IX. Saponification can be accomplished using sodium, lithium,or potassium hydroxide under aqueous conditions with an organicco-solvent such as methanol and/or tetrahydrofuran.

Scheme 4 illustrates the preparation of VIII/IX from thechloro-heterocycles X/XI via coupling with an amine (XII). In the caseof pyridazine X this coupling can be accomplished using nucleophilicdisplacement, using either strong bases (for example lithiumhexamethyldisilazide) or weak bases (for example triethylamine) in anappropriate solvent (tetrahydrofuran, acetonitrile, dimethylformamideand related). Careful monitoring of the reactions progress andappropriate solvent/base selection ensure that regioselectivity and overaddition are not a concern. In the case of triazine XI the displacementis best accomplished using a palladium-catalyzed N-arylation reaction asdescribed previously in the literature for the same compound (XI) (see:Gamier, E. et al., Synlett, 472-474 (2006)).

Scheme 5 illustrates the preparation of X, which was carried out in themanner previously described in US 2004/0142930 A1 (see: Yamada, K. etal., “Preparation of Heterocyclic Compounds as SelectivePhosphodiesterase V Inhibitors”, US 2004/0142930 A1 (Jul. 22, 2004)).

An alternative strategy that converts the ester-diol XV to the amidedichloride XVII is outlined in Scheme 6. Saponification of XV, which canbe accomplished using sodium, lithium, or potassium hydroxide underaqueous conditions with an organic co-solvent such as methanol and/ortetrahydrofuran, provides XVI. Following a chlorination procedureanalogous to that described in the preparation of X, material isrefluxed in neat phosphorus oxychloride, see US 2004/0142930 A1, butrather than quench the reaction with water, a nucleophilic amine (NH₂R¹)either used in excess or in the presence of a tertiary amine base (suchas triethylamine or diisopropylethylamine) are added to the crudeproduct to provide XVII.

Scheme 7 illustrates an alternative preparation of II. In this strategythe amine XII is coupled to the dichloride XVII. Displacement of thedihalide is most often accomplished in the presence of a strong base,such as sodium bis(trimethylsilyl)amide or lithiumbis(trimethylsilyl)amide, but it is also conceivable that it could beaccomplished using a weak base such as N,N-diisopropylethylamine (orrelated), or under elevated thermal conditions in the absence of anybase, or in the presence of an acid catalyst. In all cases a number ofsolvents could be used, including tetrahydrofuran, dimethylformamide andN-methyl-2-pyrrolidone. Due to the increased reactivity of the4-position relative to the 6-position of the 4,6-dichloropyridazineamide it is reasonable to assume that alternative strategies could alsobe envisioned by someone skilled in the art of chemical synthesis,including palladium catalyzed N-arylation of amines.

Scheme 8 illustrates the preparation of XI, which may be carried out inthe manner previously described in US 2002/0061865 A1 (see: Kramer, J.B. et al., “Pyridotriazines and Pyridopyridazines”, US 2002/0061865 A1(May 23, 2002).).

Scheme 9 illustrates how pendant sulfides can be oxidized to thecorresponding sulfones or (in the case of XXII) the sulfoxide (notillustrated). The sulfide (XXII/XXIII) can be oxidized to the sulfone(XXIV/XXV) using an oxidant such as sodium tungstate or3-chloroperbenzoic acid in an organic solvent such as dichloromethane oracetic acid. The partial oxidation of XXII to the sulfoxide (not shown)generally requires more mild conditions such as hydrogen peroxide inacetic acid; however, it is possible to use the same conditions as whentargeting the sulfone if one quenches the reaction at the appropriatetime. To access the sulfoxide in the triazene series, the sulfide group(Z) can be displaced by VII (Scheme 2) and then partial oxidation can beperformed as described above.

A large number of the anilines that were employed in Scheme 4 and Scheme7 were commercially available; however, some were not. A strategy forthe synthesis of many non-commercially available anilines is describedin Scheme 10. The commercially available XXVI can be converted to theether XXVII using the Williamson ether synthesis. The Williamson etherformation is a common protocol for the synthesis of ethers, the reactionconsists of the combination of an alcohol and a base—such as potassiumcarbonate, sodium hydride, triethylamine, or any number of others,followed by the addition of a compatible electrophile, such as analiphatic, benzylic or allylic functional group featuring a leavinggroup—most commonly a halide, but mesylates/tosylates and other groupsare also compatible, is added. The reaction is typically run in a polaraprotic solvent such as tetrahydrofuran or dimethylformamide. The nitrogroup of XXVII is then reduced to the amine (XXVIII) using aheterogeneous catalyst such as palladium, zinc or iron and a hydrogensource such as hydrogen (gas), ammonium chloride or hydrochloric acid,such reactions are typically run in alcoholic solvents. Borylation ofthe aryl bromide can be accomplished using palladium catalysis (seeIshiyama, T. et al., J. Org. Chem., 60:7508 (1995)); however, metalhalogen exchange followed by reaction with electrophilic borane isanother common approach. The boronic ester (XXIX) can be coupled via theSuzuki coupling to a wide variety of aryl and heteroaryl halides using anumber of different catalysts, ligands, bases and solvents. One commoncombination of reagents is 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride, as the catalyst, tribasic potassium phosphate (inwater), as the base, reacting with an aryl bromide using dioxane as thesolvent; however, a great number of potential combinations exist, for apartial description see: Barder, T. E. et al., J Am. Chem. Soc.,127:4685-4696 (2005); and Miyaura, N. et al., Chem. Rev., 95:2457-2483(1995).

Scheme 11 illustrates a means by which diversity at the R⁷ (Ia) can beintroduced at the end of the synthetic sequence. In this strategy XVIIand XXVIII can be coupled following the same procedures described inScheme 7. Intermediate XXX can be converted to the primary amine via theaddition of a protected amine (either via thermal, or selectivepalladium catalyzed N-arylation conditions) followed by deprotection,for example 4-methoxyphenyl)methanamine can be introduced under strictlythermal conditions followed by deprotection with a protic acid (such astrifluoroacetic acid) to provide XXXI. Addition of XXXII to the freeamine can be accomplished using the same techniques described in Scheme2. Conversion to Ia can be accomplished using the Suzuki couplingreaction as described in Scheme 10, as well as other cross-couplingstrategies such as Stille and Negishi cross-couplings (see: Stanforth,S. P., Tetrahedron, 54:263-303 (1998)).

Scheme 12 illustrates how some of heterocycles can be built directly offof carbonyl functionality to arrive at anilines XII without the use of atransition metal catalyzed coupling reaction. The commercially availableXXXIV can be converted to the ether XXXV via the techniques described inScheme 10, similarly XXXVI can be converted to XXXVII. XXXV can beconverted to the amide XXXVIII directly using ammonia and ammoniumhydroxide in methanol, or via saponification and amide formation(described in Schemes 3 and 2 respectively). The amide XXXVIII can beconverted to a triazole via formation of the amidine using reagents suchas N,N-dimethylacetamide dimethyl acetal or N,N-dimethylformamidedimethyl acetal followed by exposure to hydrazine in the presence ofacetic acid. Alternatively the tetrazole XL can be prepared from XXXVIIIby reaction with triazidochlorosilane (generated in situ fromtetrachlorosilane and sodium azide, see: E1l-Ahl, A-A. S. et al.,Tetrahedron Lett., 38:1257-1260 (1997).). The hydrazide XLI can beconverted to the oxadiazole via a condensation reaction with anorthoformate or orthoacetate under thermal or acid catalyzed conditions,often using the orthoformate/orthoacetate as the solvent. Alternativelythe aceto variant of hydrazide XLI can be converted to the thiazole byexposure to a sulfonating reagent such as Lawesson's reagent and thencondensation under thermal conditions, typically in polar aproticsolvent such as dioxane. The ketone XXXVII can be converted to thepyrazole XLIV by condensation with N,N-dimethylacetamide dimethyl acetalor N,N-dimethylformamide dimethyl acetal (or related) followed byreaction with hydrazine in the presence of acetic acid. In the cases ofXXXIX, XL, and XLIV the heterocycle can further be reacted with anelectrophile such as organo-halides, epoxides or activated carbonylspecies (under basic conditions using an inorganic base such aspotassium carbonate, a tertiary amine such as triethylamine, or a strongbase such as sodium hydride) or with vinyl ethers such as ethoxyethene(under acidic conditions). Other electrophiles such as silyl halideswould also be successful as would potentially a selective palladiumcatalyzed N-arylation. Finally the nitro compounds can be converted tothe aniline XII via reduction using conditions similar to thosedescribed in Scheme 10. This list is far from an exhaustive collectionof the heterocycles available from common functional group manipulationsof carbonyl moieties and their derivatives (such as cyanides) see:Caron, S., Practical Synthetic Organic Chemistry, 609-647 (2011) andreferences therein.

Scheme 13 illustrates the synthesis of the thio-variant of XII. Startingfrom the commercially available acid XLVI, which can be converted to theester via heating with methanol in the presence of a protic acid, aswell as by any number of techniques available for the synthesis ofesters from acids, such as formation of the acid halide (described inScheme 2) followed by reaction with methanol. Displacement of thechloride to provide XLVIII can be accomplished via nucleophilic additionusing sodium thiomethoxide. Conversion to the functionalized anilineXLIX follows the same techniques illustrated and described in Scheme 12.Additionally the final sulfide product can be oxidized to the sulfoneusing the oxidation conditions described in Scheme 9.

Scheme 14 illustrates another form of the final compound Ia. In thisstrategy the aniline L (made via reduction of the nitro compound XXXV byanalogy to Scheme 10) is added to the dichloride XVII using thetechniques from Scheme 7. Conversion to LII can be accomplished usingthe same techniques described in Scheme 1. Saponification (described inScheme 3) provides the acid LIII. The acid LIII can be converted tovarious heterocycles using the techniques described in Scheme 12, or itcan be coupled with an amine to generate the amide LV as the finalproduct as described in Scheme 2.

Scheme 15 illustrates another variant of XII, where the aniline has beensubstituted with a heterocycle via a carbon-nitrogen bond. Starting fromcommercially available XXVI an Ullmann condensation (for a recent reviewsee: Mannier, F. et al., Angew. Chem. Int. Ed., 48:6954-6971 (2009)) canbe used. This reaction is typically performed in the presence of acopper salt (such as copper(I) oxide), an inorganic base (such as cesiumcarbonate) and often a ligand (although some solvents such as DMF cantake the role of the ligand). The phenol LVI can be converted to theether LVII using the Williamson ether conditions as described in Scheme10. Conversion to the aniline (LVIII) is accomplished by reduction ofthe nitro group as described in Scheme 10.

Scheme 16 describes the synthesis of anilines LIX and LXII. ASonogashira coupling of XXVIII/XXVII with ethynyltrimethylsilanefollowed by removal of the silyl group using a mild base (such aspotassium carbonate in a protic solvent such as methanol) or a fluoridesource (such as tetrabutylammonium fluoride or potassium fluoride) canbe used to provide the terminal alkynes LIX and LX. The Sonogashiracoupling is performed using a palladium catalyst (such as tetrakistriphenylphosphine palladium), a copper catalyst such as copper(I)iodide, and a base (typically an amine base such as triethylamine ordiisopropylamine) using either the base as the solvent or a polarsolvent such as dimethylformamide; however, a great deal of work hasbeen done running the reaction with different ligands and additives andeven in the absence of the catalysts, see: Chinchilla, R. et al., Chem.Rev. 107:874-923 (2007); Chinchilla, R. et al., Chem. Soc. Rev.,40:5084-5121 (2011). The aniline LIX can be coupled to XVII as describedin Scheme 7 and then converted to the target ligand I as described inScheme 1 or further elaborated using the techniques described for LXI(to follow). LX can be converted to the 1,2,3-triazole using the Huisgencycloaddition (or “Click chemistry”), This reaction is run between analkyne and an azide using a copper catalyst (commonly copper(II)sulfate), a reducing agent (such as sodium ascorbate), the reaction canbe run in a number of solvents/co-solvents including water, tert-butylalcohol, tetrahydrofuran and toluene. A great deal of work has been donedescribing the variety and versatility of this cycloaddition, forreviews see: Kolb, H. C. et al., Angew. Chem. Int. Ed., 40:2004-2021(2001), and Meldal, M. et al., Chem. Rev., 108:2952-3015 (2008). If theHuisgen cycloaddition is performed with a removable group such as methylpivalate this can be removed and the triazole alkylated as described inScheme 12. Otherwise the nitro group can be reduced as described inScheme 10 and LXII can be carried forward to react with XVII asdescribed in Scheme 7.

Scheme 17 illustrates the synthesis of penultimate compounds LXV(converted to target ligands using the coupling procedures described inScheme 1). Intermediate LXIII (prepared using the techniques describedin Scheme 16 and Scheme 7) can be converted to the isoxazole LXV using a[3+2] cycloaddition with a nitrile oxide (formed in situ from aN-hydroxyimidoyl chloride and a mild non-nucleophilic base). Thereaction can be run thermally in aprotic solvents (such asdichloroethane) but recent work has described the utility of catalystsin the reaction, see: Grecian, S. et al., Angew. Chem. Int. Ed.,47:8285-8287 (2008).

Scheme 18 illustrates the synthesis of target compounds LXX and LXXI.Commercially available LXVI can be converted to the aniline LXVIIIfollowing the strategies outlined in Scheme 10. Addition of LXVIII toXVII follows the techniques described in Scheme 7 to provide LXIX whichcan be coupled to amines IV following the strategies described inScheme 1. Conversion of the cyano-containing LXX to the oxadiazole LXXIcan be accomplished via the nucleophilic addition of hydroxylamine tothe cyanide, performed under basic conditions typically in a polarprotic solvent such as water or alcohol, followed by acylation andcondensation with acetic anhydride, done by heating the intermediatewith acetic anhydride in a polar aprotic solvent such as dioxane.

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in thepreparation of compounds of Formula (I), can be prepared usingprocedures shown in the following Examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these Examples, are not meant to be limiting, but are meantto demonstrate how the compounds of Formula (I) can be prepared.Starting materials and reagents used in these examples, when notprepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature.

In the Examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being prepared).Column chromatography was performed with pre-packed silica gelcartridges using an Isco medium pressure chromatography apparatus(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. Chemical names were determined using ChemDraw Ultra, version9.0.5 (CambridgeSoft). The following abbreviations are used:

NaHCO₃ (aq)=saturated aqueous sodium bicarbonatebrine=saturated aqueous sodium chlorideDCM=dichloromethane

DIEA=N,N-diisopropylethylamine DMAP=4-(N,N-dimethylamino)pyridineDMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxideEDC=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochlorideEtOAc=ethyl acetateHOAT=1-hydroxy-7-azabenzotriazoleHOBT=1-hydroxybenzotriazole hydratert=ambient room temperature (generally about 20-25° C.)TEA=triethylamineTFA=trifluoroacetic acidTHF=tetrahydrofuran

Preparations

The preparations set out below are for the synthesis of reagents thatwere not obtained from commercial sources and were employed for thepreparation of compounds of formula I of the invention. All chiralcompounds in the Tables and Schemes are racemic unless specifiedotherwise.

Reverse-phase preparative high performance liquid chromatography(“HPLC”) was performed with Shimadzu 8A liquid chromatographs using YMCS5 ODS columns (20×100, 20×250, or 30×250 millimeter (“mm”)). Gradientelution was performed with methanol (“MeOH”)/water mixtures in thepresence of 0.1% trifluoroacetic acid (“TFA”).

Analytical HPLC Method Employed in Characterization of Examples

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographsusing the following methods:

Method A (used in all cases, unless otherwise indicated):

Linear gradient of 0 to 100% solvent B over 4 minutes (“min”), with 1minute (“min”) hold at 100% B

Ultraviolet (“UV”) visualization at 220 nanometers (“nm”)

Column: YMC S5 ODS Ballistic 4.6×50 mm

Flow rate: 4 milliliters (“mL”)/min

Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol

Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water

Method B:

Column: PHENOMENEX® Luna C18(2), 4.6×50 mm×5 m

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)    -   Detector 3: ELSD

Method C:

Column: Waters SunFire C18, 4.6×50 mm×5 m

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)    -   Detector 3: ELSD

Method D:

Column: PHENOMENEX® Luna C18(2), 4.6×50 mm×5 m

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)    -   Detector 3: ELSD

Method E:

Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 m particles

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 10 mM ammonium acetate

Gradient Range: 0-100% B

Gradient Time: 3 min

Flow Rate: 1.11 mL/min

Analysis Time: 4 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)    -   Detector 3: ELSD

Method F:

Column: Waters SunFire C18 (4.6×150 mm), 3.5 m

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 12 min

Flow Rate: 4 mL/min

Analysis Time: 15 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: UV at 254 nm

Method G:

Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 m particles

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.05% TFA

Gradient Range: 0-100% B

Gradient Time: 3 min

Flow Rate: 1.11 mL/min

Analysis Time: 4 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI⁺)    -   Detector 3: ELSD

Method H:

Column: (LCMS) Ascentis Express C18, 4.6×50 mm, 2.7 m particles

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 10 mM ammonium acetate

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI⁺⁾

Method I:

Column: Waters XBridge C18, 4.6×50 mm, 5 μm particles

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.05% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI⁺⁾

Method J:

Column: (LCMS) BEH C18, 2.1×50 mm, 1.7 m particles

Mobile Phase: (A) water; (B) acetonitrile

Buffer: 0.05% TFA

Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min) 98%-2% B (to1.6 min)

Gradient Time: 1.6 min

Flow Rate: 0.8 mL/min

Analysis Time: 2.2 min

Detection:

-   -   Detector 1: UV at 254 nm    -   Detector 2: MS(ESI⁺⁾

Method K:

Column: (LCMS) BEH C18, 3.0×50 mm, 1.7 μm particles

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 10 mM ammonium acetate

Gradient Range: 0-100% B

Gradient Time: 1.8 min

Flow Rate: 1.2 mL/min

Analysis Time: 4 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI⁺⁾

Method L:

Column: (LCMS) SunFire C18 2.1×30 mm, 2.5 μm particles

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 2 min

Flow Rate: 1 mL/min

Analysis Time: 3 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)

Method M:

Column: (LCMS) SunFire C18 2.1×30 mm, 3.5 m particles

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 1 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)

Method N:

Column: Waters SunFire C18 (3×150 mm), 3.5 m

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.05% TFA

Gradient Range: 0-100% B

Gradient Time: 12 min

Flow Rate: 0.5 mL/min

Analysis Time: 15 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: UV at 254 nm

Method O:

Column: Waters SunFire C18 (4.6×150 mm), 3.5 m

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.05% TFA

Gradient Range: 0-50% B (0-15 min) 50-100% B (15-18 min)

Gradient Time: 18 min

Flow Rate: 1 mL/min

Analysis Time: 23 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: UV at 254 nm

Method P:

Column: XBridge phenyl (4.6×150 mm), 3.5 m

Mobile Phase: (A) 5:95 acetonitrile:water; (B) 95:5 acetonitrile:water

Buffer: 0.05% TFA

Gradient Range: 10-100% B

Gradient Time: 12 min

Flow Rate: 1 mL/min

Analysis Time: 15 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: UV at 254 nm

Method Q:

Column: YMC COMBISCREEN® ODS-A, 4.6×50 mm, S-5

Mobile Phase: (A) 10:90 methanol:water; (B) 90:10 methanol:water

Buffer: 0.1% TFA

Gradient Range: 0-100% B

Gradient Time: 4 min

Flow Rate: 4 mL/min

Analysis Time: 5 min

Detection:

-   -   Detector 1: UV at 254 nm

Method R:

Column: (LCMS) Ascentis Express C18, 2.1×50 mm, 2.7 μm particles

Mobile Phase: (A) 2:98 acetonitrile:water; (B) 98:2 acetonitrile:water

Buffer: 10 mM ammonium acetate

Gradient Range: 0-100% B

Gradient Time: 1.7 min

Flow Rate: 1 mL/min

Analysis Time: 4 min

Detection:

-   -   Detector 1: UV at 220 nm    -   Detector 2: MS(ESI+)

Step 1

To a cooled (0° C.) mixture of diethyl 1,3-acetonedicarboxylate (12.4mL, 68.3 mmol) and triethylamine (10.5 mL, 75 mmol) in acetonitrile (270mL) was added 4-acetamidobenzenesulfonylazide (16.74 g, 69.7 mmol) inportions. The reaction was warmed to room temperature and stirred for 1hour, at which point the solids were removed by filtration, rinsing with1:1 heptanes:diethyl ether. The filtrate was concentrated and thenre-dissolved in 1:1 heptanes:diethyl ether. The slurry was stirred for30 minutes, filtered and the filtrate concentrated once more to providethe crude product Int1 (12.2 g, 50.8 mmol). ¹H NMR (400 MHz,chloroform-d) δ 4.31 (q, J=7.2 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.87 (s,2H), 1.33 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H).

Step 2

Int1 (12.2 g, 50.8 mmol) was dissolved in diethyl ether (100 mL) andtriphenylphosphine (14 g, 53.5 mmol) was added. The reaction was stirredovernight at room temperature and then concentrated in vacuo. To theresidual sludge was added acetic acid (100 mL) and water (10 mL), thevessel was equipped with a condenser and heated to reflux for 6 hours,and then concentrated in vacuo. The crude sludge was purified byautomated chromatography (DCM/MeOH) and then by titration with diethylether (x2) to provide Int2 (5.25 g, 28.5 mmol). ¹H NMR (400 MHz,chloroform-d) δ 12.30 (br. s., 1H), 10.59 (br. s., 1H), 6.31 (s, 1H),4.51 (q, J=7.0 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H). LC retention time 0.52[J]. MS(E⁺) m/z: 185 (MH⁺).

Step 3

To a 350 mL nitrogen purged Schlenk flask containing Int2 (3.77 g, 20.47mmol) was added phosphorus oxychloride (38 mL, 408 mmol). The vessel wassealed and heated to 100° C. for 3.5 hours. The reaction was cooled toroom temperature and the excess phosphorus oxychloride was removed invacuo. The crude oil was dissolved into chloroform, re-concentrated andthen poured into ice water, rinsing with ethyl acetate. The two layerswere transferred to a separatory funnel, separated and the aqueous layerextracted 3× with ethyl acetate. The combined organic layers were washedtwice with water and once with brine (saturated aqueous sodium chloride)and then dried over sodium sulfate, filtered, concentrated and thenpurified by automated chromatography (5-90% EtOAc:hexanes), providingInt3 (3.64 g, 16.3 mmol). ¹H NMR (400 MHz, chloroform-d) δ 7.70 (s, 1H),4.55 (qd, J=7.1, 1.1 Hz, 2H), 1.46 (td, J=7.2, 0.9 Hz, 3H). LC retentiontime 0.79 [J]. MS(E⁺) m/z: 221 (MH⁺).

Step 4

A vial was equipped with Int3 (100 mg, 0.45 mmol),2-(methylthio)aniline, triethylamine (0.19 mL, 1.36 mmol) andacetonitrile (0.5 mL), sealed, and heated to 100° C. overnight. Thesolvent was then removed under vacuum and the crude material purified bysilica gel chromatography (0% to 50% EtOAc:hexanes) to provide Int4 (65mg, 0.20 mmol). Note that the regiochemistry of the series was verifiedby a crystal structure of Int4. ¹H NMR (400 MHz, chloroform-d) δ 9.66(br. s., 1H), 7.39-7.33 (m, 2H), 6.81 (s, 1H), 4.58 (q, J=7.1 Hz, 2H),2.46 (s, 3H), 1.52 (t, J=7.2 Hz, 3H). LC retention time 0.96 [J]. MS(E⁺)m/z: 324 (MH⁺).

Step 5

Int4 (65 mg, 0.20 mmol) was dissolved in tetrahydrofuran (THF, 2 mL) andlithium hydroxide (2 M in water, 0.40 mL, 0.80 mmol) was added. Afterstirring 30 min at room temperature, the THF was removed under reducedpressure. The residual solution was diluted with water and thenacidified with 1 M hydrochloric acid. The product was extracted threetimes with ethyl acetate and then the combined organic layers were driedover sodium sulfate, filtered and concentrated. The residual acid wasthen dissolved in N,N-dimethylformamide (DMF, 0.9 mL) anddeuteromethylamine (HCl salt, 16 mg, 0.23 mmol, Aldrich, catalog number176001, 99 atom % D), triethylamine (0.10 mL, 0.58 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 88 mg, 0.23 mmol) were added. The reactionwas stirred for 90 minutes and then diluted with water (˜15 mL)resulting in a beige precipitate. The precipitate was collected byfiltration, rinsing with water and then hexanes to provide Int5 (33 mg,0.095 mmol). ¹H NMR (500 MHz, chloroform-d) δ 10.69 (br. s., 1H), 8.20(br. s., 1H), 7.38-7.28 (m, 2H), 7.28-7.21 (m, 2H), 6.80 (s, 1H), 1.26(s, 3H). LC retention time 0.97 [J]. MS(E⁺) m/z: 312 (MH⁺).

Step 6

Int5 (52 mg, 0.17 mmol) was dissolved in acetic acid (1.7 mL) andhydrogen peroxide (30% aqueous solution, 0.34 mL, 3.34 mmol) and sodiumtungstate dihydrate (55 mg, 0.17 mmol) were added. The reaction wasstirred at room temperature for 40 minutes and then water was added andthe product was extracted with ethyl acetate (x3). The combined organiclayers were washed with water, dried over sodium sulfate, filtered,concentrated and then purified by automated chromatography (20%-100%EtOAc:hexanes) to provide Int6. ¹H NMR (400 MHz, chloroform-d) δ 11.49(s, 1H), 8.20 (br. s., 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 7.72 (td,J=7.8, 1.4 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.50-7.43 (m, 1H), 7.15 (s,1H), 3.11 (s, 3H). LC retention time 0.81 [J]. MS(E⁺) m/z: 344 (MH⁺).

Alternatively Int5 can be prepared as follows:

Step 1

Int1 (41.6 g, 182 mmol) was dissolved in diethyl ether (300 mL) andtriphenylphosphine (47.8 g, 182 mmol) was added. The reaction wasstirred overnight at room temperature and then concentrated in vacuo. Tothe residual sludge was added acetic acid (300 mL) and water (30 mL),the vessel was equipped with a condenser and heated to reflux for 6hours. The reaction was concentrated and then dissolved in1,2-dichloroethane (300 mL) and re-concentrated. The resultant slurrywas dissolved in THF (600 mL) and MeOH (200 mL) and then LiOH (3M aq.201 mL, 602 mmol) was added in portions over 5 minutes. After overnightstirring the reaction was concentrated to remove the organic solvents.Water and 1 M NaOH was added to generate a homogenous solution (totalvolume=400 mL, pH˜12). The aqueous layer was washed 2× with diethylether and 2× with dichloromethane. Concentrated HCl was added until pH˜7and then the water was removed under reduced pressure, leaving a volumeof ˜50 mL, to this was added, at 0° C., concentrated HCl until thesuspension became a densely packed solid. This solid was filtered,rinsing with 1 M HCl and then dichloromethane. After air drying (pullingair through the material on the filter pad) overnight the solid wasdried for 3-5 days under vacuum in a dessicator over phosphorouspentoxide providing 27.5 g (97%) of Int7. ¹H NMR (400 MHz, deuteriumoxide) δ 6.05 (s, 1H). LC retention time 6.27 [N]. MS(E⁺) m/z: 157(MH⁺).

Step 2

Int7 (10 g, 64.1 mmol) was placed in a 1 L RBF and triethylamine (8.9mL, 64.1 mmol) was added, followed by phosphorus oxychloride (50 mL, 546mmol). A water cooled condenser equipped with a drying tube (24/40 jointsize) was then attached. The flask was placed in a room temperature oilbath and once self-reflux ceased, the temperature was raised to 80° C.Once that temperature was reached and the vigorous reflux subsided thetemperature was raised again to 110° C. and the reaction run for 120minutes. The heating was stopped and the reaction allowed to cool to˜90° C. (oil bath temperature), at which point 200 mL of anhydrous1,2-dichloroethane was added and the flask was concentrated underreduced pressure. Caution was taken in the disposal of the condensate,which contained phosphorous oxychloride. Thus, all of the distillateswere poured slowly and portionwise into a rapidly stirred ethanol/icebath. Next, 200 mL of anhydrous 1,2-dichloroethane was added to theresidue and the mixture sonicated and then concentrated. Finally 300 mLof anhydrous 1,2-dichloroethane was added and the sides of the vesselwere scraped into the liqueur, the system was sonicated and stirred for˜10 minutes, and then filtered through CELITE® packed withdichloromethane and the pad rinsed with dichloromethane until the totalfiltrate volume was ˜800 mL. This was transferred to a 2 L RBF and thesolvent was removed. Next the residue was dissolved in THF (200 mL),deuteromethylamine (HCl salt, 2.26 g, 32 mmol) was then added followedby N,N′-diisopropylethylamine (18 mL, 103 mmol). After 1 hour thereaction was concentrated and the residue adsorbed onto CELITE® usingdichloromethane. The CELITE® was dried and transferred onto amedium-grade glass frit, the crude product was flushed off of theCELITE® using EtOAc and the filtrate re-concentrated, and thenre-adsorbed onto CELITE® using dichloromethane. This material could thenbe purified using automated chromatography with dry loading. Purefractions were combined to provide 4.56 g (33%) of Int8. ¹H NMR (500MHz, chloroform-d) δ 7.72 (s, 1H). LC retention time 0.72 [A]. MS(E⁺)m/z: 209 (MH⁺).

Step 3

Int8 (3.19 g, 15.26 mmol) was dissolved in THF (100 mL) and2-(methylthio)aniline (2.10 mL, 16.8 mmol) was added. To this solutionat room temperature was added sodium bis(trimethylsilyl)amide (NaHMDS, 1M in THF, 38 mL, 38 mmol) in a dropwise manner. The reaction was stirredfor 15 minutes and then 22 mL of 1 M (aq.) HCl was added to quench thereaction. The resultant homogenous solution was poured into rapidlystirred water (600 mL) resulting in a white precipitate. The suspensionwas stirred for 10 minutes and then filtered, rinsing with water andthen hexanes. The powder was dried and carried on as Int5. ¹H NMR (400MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.34 (s, 1H), 7.47-7.41 (m, 2H), 7.37(td, J=7.7, 1.3 Hz, 1H), 7.32-7.25 (m, 1H), 6.80 (s, 1H), 2.46 (s, 3H).

Example 1

5-Fluoro-4-methylpyridin-2-amine (22 mg, 0.18 mmol) was combined withInt6 (15 mg, 0.044 mmol). To the vessel was added dimethylacetamide(DMA, 0.5 mL) followed by tris(dibenzylideneacetone)dipalladium(0)(Pd₂(dba)₃, 6.0 mg, 0.0065 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 7.6 mg, 0.013mmol) and cesium carbonate (57 mg, 0.18 mmol). The vessel was thenevacuated and backfilled with nitrogen three times and then heated to145° C. for 4.5 hours. The crude product was diluted with DMF andfiltered, and then purified using preparative HPLC. The pure fractionswere pooled and concentrated in vacuo to a volume of about 2 mL at whichpoint saturated aqueous sodium bicarbonate was added and the slurrystirred for 10 minutes. The product was extracted with ethyl acetate(x5), the combined organic layers were washed with deionized water,dried over sodium sulfate, filtered and concentrated. The residual solidwas dissolved in 2:1 acetonitrile:water, frozen and then dried on alyopholizer overnight to provide 1 (8.4 mg, 0.019 mmol). ¹H NMR (500MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.78 (dd, J=8.0,7.8 Hz, 1H), 7.63 (s, 1H), 7.34 (s, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.00(dd, J=8.0, 7.8 Hz, 1H), 3.09 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 2.13 (s,3H). LC retention time 0.68 [J]. MS(E⁺) m/z: 434 (MH⁺).

The following Examples were prepared in a similar manner to the productof Example 1:

Example Rt (min) m/z No. R¹ R² [Method] [M + H]⁺  2 H

 1.37 [E] 403  3 CH₃

 1.46 [E] 417  4

 1.50 [E] 431  5

 1.54 [A] 443  6 CD₃

 0.73 [J] 420  7 CD₃

 1.18 [E] 431  8 CD₃

 1.14 [E] 417  9 CH₃

 1.28 417 10 CH₃

 1.08 414 11 CH₃

 1.24 424 12 CH₃

 1.04 390 13 CH₃

 1.50 449 14 CH₃

 1.30 413 15 CH₃

 1.45 431 16 CD₃

 1.30 [E] 402 17 CD₃

 1.22 [E] 393 18 H

 6.25 [N] 417 19 CD₃

 1.00 [E] 417 20 CD₃

 1.45 [E] 430 21 CD₃

 1.08 [E] 431 22 CD₃

 1.37 [E] 432 23 CD₃

 1.46 [E] 416 24 CD₃

 0.63 [J] 419 25 CD₃

 0.64 [J] 427 26 CD₃

 1.51 [E] 441 27 H

 5.58 [N] 385 28 CD₃

 1.08 [E] 411 29 CD₃

 1.21 [E] 487 30 CD₃

 1.56 [E] 416 31 CH₃

10.61 [O] 399 32 CD₃

 1.46 [E] 460 33 CD₃

 1.39 [E] 444 34 CD₃

 1.04 [E] 432 35 CD₃

 1.64 [E] 470 36 CD₃

 1.54 [E] 430 37 CD₃

 1.48 [E] 446 38 CD₃

 1.31 [E] 432 39 CD₃

 1.02 [E] 417 40 CD₃

 1.13 [E] 461 41 CD₃

 1.15 [E] 461 42 CD₃

 1.18 [E] 433 43 CD₃

 1.27 [E] 447 44 CD₃

 1.72 [E] 475 45 CD₃

 1.59 [E] 461 46 CD₃

 1.25 [E] 431 47 CD₃

 1.32 [E] 445 48 CD₃

 1.18 [E] 446 49 CD₃

 0.96 [E] 432 50 CD₃

 1.18 [E] 460 51 CD₃

 1.32 [E] 446

Step 1

2-Bromo-6-nitrophenol (5.0 g, 22.9 mmol) was dissolved in DMF (3 mL),potassium carbonate (4.75 g, 34.4 mmol) was added and the reaction wasstirred for 30 minutes. Next iodomethane (2.15 mL, 34.4 mmol) was addedand the reaction was stirred overnight. The crude reaction was filtered,diluted with ethyl acetate and washed with brine (twice) and water(twice). The organic layer was dried over sodium sulfate, filtered andconcentrated to provide Int9 (5.12 g, 96%). LC retention time 0.92 [J].

Step 2

Int9 (5.12 g, 22.1 mmol) was dissolved in ethyl alcohol (150 mL) andwater (50 mL). To this was added zinc (5.77 g, 88 mmol) and ammoniumchloride (2.36 g, 44.1 mmol). The reaction was stirred for 1 hour,filtered and then concentrated. The crude material was dissolved inethyl acetate and washed with water three times, the organic layer wasthen dried over sodium sulfate, filtered, concentrated and collected(4.3 g, 96%). LC retention time 0.75 [J]. m/z: 201.8 (MH⁺).

Step 3

Int10 (2.0 g, 9.9 mmol) was dissolved in dioxane (40 mL) and the vesselpurged with nitrogen for 5 minutes. Next bis(pinacolato)diborone (3.77g, 14.85 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (404 mg, 0.49 mmol) and potassiumacetate (2.91 g, 29.7 mmol) were added. The flask was evacuated andbackfilled with nitrogen, and then heated to 100° C. for 15 hours. Waterwas added to quench the reaction and the product was then extracted withEtOAc. The combined organic layers were washed with brine (x3), driedover sodium sulfate, filtered, concentrated and purified using automatedchromatography (elutes at ˜40% ethyl acetate) to provide Int11 (2.0 g,81%). ¹H NMR (400 MHz, chloroform-d) δ 7.12 (dd, J=7.3, 1.8 Hz, 1H),6.96-6.89 (m, 1H), 6.88-6.83 (m, 1H), 3.82 (s, 3H), 1.37 (s, 12H). LCretention time 0.65 [J]. m/z: 250 (MH⁺).

A stirred mixture of 2-bromo-4-methylthiazole (201 mg, 1.13 mmol), Int11(309 mg, 1.24 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (36.8 mg in dioxane (8 mL) was degassed by bubblingnitrogen through the mixture for 5 minutes. Subsequently tribasicpotassium phosphate (2M in water, 1.69 mL, 3.39 mmol) was added and thereaction mixture heated at 100° C. for one hour. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate (75 mL) andthen dried over sodium sulfate, filtered, concentrated and purified byautomated chromatography providing Int12 (218 mg, 83%). ¹H NMR (400 MHz,chloroform-d) δ 7.63 (dd, J=7.9, 1.6 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H),6.96 (d, J=1.0 Hz, 1H), 6.80 (dd, J=7.8, 1.5 Hz, 1H), 3.88 (br. s., 2H),3.80 (s, 3H), 2.53 (d, J=1.0 Hz, 3H). LC retention time 0.65 [J]. m/z:221 (MH⁺).

Step 1

A vial containing 2-bromo-6-nitrophenol (290 mg, 1.33 mmol), 1H-pyrazole(136 mg, 2.00 mmol) and copper(I) oxide (190 mg, 1.33 mmol) in DMF (3mL) was purged with nitrogen for 5 minutes. Cesium carbonate (867 mg,2.66 mmol) was then added and the vessel was sealed and heated to 100°C. overnight. The reaction was filtered, concentrated and carried onwithout further purification.

Step 2

The crude product of Step 1 was dissolved in DMF (3 mL), potassiumcarbonate (269 mg, 2.0 mmol) was added and the reaction was stirred for30 minutes. Next iodomethane (0.12 mL, 2.0 mmol) was added and thereaction was stirred for 2 hours. The crude product was filtered,concentrated and purified by automated chromatography providing1-(2-methoxy-3-nitrophenyl)-1H-pyrazole (115 mg, 39% yield). LCretention time 1.34 [J].

Step 3

1-(2-Methoxy-3-nitrophenyl)-1H-pyrazole (230 mg, 1.05 mmol) wasdissolved in ethanol (3 mL). To this was added zinc (274 mg, 4.2 mmol),ammonium chloride (112 mg, 2.10 mmol) and water (1 mL). The reaction wasstirred for 2 hours, filtered, concentrated and purified by automatedchromatography to provide 2-methoxy-3-(1H-pyrazol-1-yl)aniline (150 mg,76% yield). LC retention time 0.68 [J]. 190 (MH⁺).

Step 1

A mixture of 1-bromo-2-methoxy-3-nitrobenzene (577 mg, 2.487 mmol),bis(triphenylphosphine)palladium(II) chloride (175 mg, 0.249 mmol), andcopper(I) iodide (189 mg, 0.995 mmol) in DMA (10 mL) in a pressurevessel was stirred at room temperature and degassed by bubbling drynitrogen through it for 5 minutes. Then ethynyltrimethylsilane (1.757mL, 12.43 mmol) and bis(isopropyl)amine (7.74 mL, 54.7 mmol) were addedand the reaction mixture immediately became a yellow solution. Thevessel was then sealed and placed into a warm 105° C. bath. Stirred at105° C. overnight. After stirring overnight, evaporated away thediisopropylamine and the excess TMS-acetylene, then diluted with 150 mLethyl acetate. Washed the organic solution once with 1:1 ammoniumhydroxide:sat. ammonium chloride, once with saturated ammonium chloride,once with 10% aqueous LiCl, and once with brine. The organic layer wasthen dried over sodium sulfate, filtered, concentrated, and loaded ontoa 24 g silica gel column for purification by flash chromatography,eluting with 0-100% EtOAc in hexanes. Afforded((2-methoxy-3-nitrophenyl)ethynyl)trimethylsilane (177 mg, 28% yield) asan impure brown oil.

Step 2

A mixture of ((2-methoxy-3-nitrophenyl)ethynyl)trimethylsilane (177 mg,0.710 mmol) and potassium carbonate (294 mg, 2.130 mmol) in methanol (7mL) was stirred at room temperature for 30 minutes. At which point thereaction was partitioned between EtOAc (50 mL) and water (25 mL). Thelayers were separated and the aqueous layer was extracted once withEtOAc, the combined organic layers were then washed saturated ammoniumchloride and brine. The organic layer was dried over sodium sulfate,filtered and concentrated. The resultant oil was loaded onto a 12 gsilica gel column, then purified by flash chromatography, eluting with0-10% MeOH in dichloromethane. Afforded1-ethynyl-2-methoxy-3-nitrobenzene (74 mg, 0.397 mmol, 55.9% yield) as abrown oil.

Step 3

Benzoic acid (2 mg, 0.016 mmol), L-ascorbic acid sodium salt (2 mg,10.10 mol), and copper(II) sulfate (2 mg, 0.013 mmol) were all weighedinto the small flask containing 1-ethynyl-2-methoxy-3-nitrobenzene (74mg, 0.418 mmol). A solution of azidomethyl pivalate (197 mg, 1.253 mmol)in tert-butyl alcohol (1.5 mL) and water (1.5 mL) was added and themixture was stirred at room temperature. After 20 minutes, the reactionwas complete. The reaction was diluted with 50 mL dichloromethane,washed with water, and once with 1:1 water:brine. The organic layer wasdried over sodium sulfate, then filtered, concentrated, and loaded ontoa 12 g ISCO column for purification by flash chromatography, elutingwith 0-100% EtOAc in hexanes. Afforded(4-(2-methoxy-3-nitrophenyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (116mg, 0.333 mmol, 80% yield) as a tan solid. ¹H NMR (400 MHz,chloroform-d) δ 8.27 (s, 1H), 7.59 (dd, J=7.9, 1.5 Hz, 1H), 7.06-7.01(m, 1H), 6.76 (dd, J=7.9, 1.5 Hz, 1H), 6.32 (s, 2H), 3.66 (s, 3H), 1.20(s, 9H).

Step 4

To a solution of(4-(2-methoxy-3-nitrophenyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (76mg, 0.227 mmol) in methanol (1 mL) and tetrahydrofuran (1.000 mL) wasadded sodium hydroxide (1N in water, 0.491 mL, 0.491 mmol). The solutionwas stirred at room temperature. After 10 minutes, the de-protection wascomplete. The reaction was neutralized with 0.75 mL 1M (aq.) HCl, andthen concentrated to a solid. Afforded4-(2-methoxy-3-nitrophenyl)-1H-1,2,3-triazole (50 mg, 0.204 mmol, 90%yield) as an off-white solid.

Step 5

To a solution of 4-(2-methoxy-3-nitrophenyl)-1H-1,2,3-triazole (50 mg,0.227 mmol) in DMF (2 mL) was added portionwise cesium carbonate (222mg, 0.681 mmol), followed by iodomethane (0.031 mL, 0.500 mmol). Themixture was stirred for 1 hour at room temperature. The reaction wasquenched with water (10 mL) and extracted with ethyl acetate. Washedcombined organic layers with brine, then dried over sodium sulfate. Thematerial was filtered, concentrated, and loaded onto a 12 g silicacolumn for purification by flash chromatography. Eluted with 0-100%EtOAc in hexanes. (Note: regiochemistry was confirmed bycrystallography).

Afforded Isomer A:4-(2-Methoxy-3-nitrophenyl)-1-methyl-2H-1,2,3-triazole (19 mg, 0.081mmol, 36% yield).

¹H NMR (400 MHz, chloroform-d) δ 8.04 (s, 1H), 7.27 (d, J=1.6 Hz, 1H),7.04-6.98 (m, 1H), 6.78 (dd, J=7.8, 1.6 Hz, 1H), 4.27 (s, 3H), 3.70 (s,3H).

Isomer B: 4-(2-Methoxy-3-nitrophenyl)-2-methyl-1H-1,2,3-triazole (6 mg,0.026 mmol, 11% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.02 (s, 1H),7.62-7.58 (m, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.77 (dd, J=7.8, 1.6 Hz, 1H),4.19 (s, 3H), 3.70 (s, 3H).

Step 6

Isomer A: A mixture of4-(2-methoxy-3-nitrophenyl)-1-methyl-2H-1,2,3-triazole (20 mg, 0.085mmol), zinc (55.8 mg, 0.854 mmol) and ammonium chloride (45.7 mg, 0.854mmol) in EtOH (1 mL) and water (0.143 mL) was stirred at roomtemperature for 1 hr. The reaction was then diluted with dichloromethane(50 ml), and filtered. The filtrate was washed with water (50 ml), driedover sodium sulfate, and concentrated to afford2-methoxy-3-(1-methyl-2H-1,2,3-triazol-4-yl)aniline (16 mg, 0.074 mmol,87% yield). This was used without further purification in the next step.

Isomer B: A mixture of4-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,3-triazole (21 mg, 0.09mmol), zinc (58.6 mg, 0.897 mmol) and ammonium chloride (48 mg, 0.897mmol) in EtOH (1 mL) and water (0.143 mL) was stirred at roomtemperature for 1 hr. The reaction was then diluted with dichloromethane(50 ml), and filtered. The filtrate was washed with water (50 ml), driedover sodium sulfate, and concentrated to afford2-methoxy-3-(1-methyl-1H-1,2,3-triazol-4-yl)aniline (19 mg, 0.084 mmol,93% yield). Used as is in the next step.

Step 1

2-Methoxy-3-((trimethylsilyl)ethynyl)aniline (231 mg, 0.79 mmol, 59%yield) was prepared in exactly the same manner as Preparation 6,substituting 3-bromo-2-methoxyaniline (268 mg, 1.326 mmol) as thestarting material in place of the 1-bromo-2-methoxy-3-nitrobenzene.

Step 2

A mixture of 2-methoxy-3-((trimethylsilyl)ethynyl)aniline (253 mg, 1.153mmol) and potassium carbonate (478 mg, 3.46 mmol) in methanol (5 mL) wasstirred at room temperature for 30 minutes. After 30 minutes, thereaction was complete. The reaction was partitioned between EtOAc (50mL) and water (25 mL). The layers were separated and the aqueous layerextracted with EtOAc, then the combined organic layers were washed withsaturated ammonium chloride and brine. The organic layer was dried oversodium sulfate, then filtered and concentrated. The resulting oil wasloaded onto a 12 g silica gel column, and then purified by flashchromatography, eluting with 0-10% MeOH indichloromethane. Afforded3-ethynyl-2-methoxyaniline (75 mg, 0.510 mmol, 44.2% yield) as a brownoil.

Step 1

Concentrated (30-35%) aqueous ammonium hydroxide (100 mL) was added tomethyl 2-hydroxy-3-nitrobenzoate (12 g, 60.9 mmol) and the resultingorange partial slurry was allowed to stir at room temperature overnight.The reaction was worked up by concentrating under vacuum to yield ared-orange semi-solid to which was added water (˜200 mL) and acetic acid(˜15 mL) and the slurry was stirred for 1-2 hours and filtered tocollect the solid, which was rinsed with water and dried to afford 9.42g (85%) of a pale yellow solid as the pure product. LC retention time0.59 minutes [J].

Step 2

To a solution of 2-hydroxy-3-nitrobenzamide (1 g, 5.49 mmol) in DMF (10mL) was added potassium carbonate (2.276 g, 16.47 mmol) and the mixturewas stirred at room temperature for 5 min giving an orange slurry.2-chloro-2,2-difluoroacetic acid (0.603 mL, 7.14 mmol) was then slowlyadded causing some effervescence. The reaction was stirred at roomtemperature for an additional 5 minutes, and then heated to 100° C. for˜1 h. The reaction was then cooled to room temperature, diluted withwater (˜25 mL) and extracted with EtOAc (3×20 mL) and the combinedextracts were dried over anhydrous sodium sulfate. The extracts wereconcentrated to give the crude product as a brown liquid containingresidual DMA. The crude product was dissolved into a minimal amount ofdichloromethane and was loaded onto a 4 g silica gel cartridge and waseluted with EtOAc/hexanes as the eluent. Afforded 0.58 g (46%) of ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (dd, J=8.0, 1.7 Hz, 1H),8.03 (br. s., 1H), 7.87 (dd, J=7.7, 1.5 Hz, 1H), 7.80 (br. s., 1H), 7.62(t, J=7.9 Hz, 1H), 7.34-6.89 (m, 1H).

Step 3

A solution of 2-(difluoromethoxy)-3-nitrobenzamide (0.58 g, 2.498 mmol)in EtOH (20 mL) was sparged with nitrogen for a few minutes beforeadding Pd/C (0.266 g, 0.125 mmol) then the flask was purged withhydrogen gas using a balloon and the mixture was stirred at roomtemperature for ˜2 h under hydrogen. The mixture was sparged withnitrogen to remove the hydrogen and the mixture was filtered throughCELITE® and the resulting clear, nearly colorless filtrate wasconcentrated under vacuum overnight. Afforded 503 mg of a light greycolored solid as the product. Material was used as is without anyfurther purification. ¹H NMR (400 MHz, methanol-d₄) δ 7.11-7.04 (m, 1H),6.94 (dd, J=8.0, 1.7 Hz, 1H), 6.90-6.85 (m, 1H), 6.68 (t, J=75.2 Hz,1H).

Step 1

To a solution of methyl 2-hydroxy-3-nitrobenzoate (10 g, 50.7 mmol) inDMF (100 mL) at room temperature was added potassium carbonate (14.02 g,101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) andthe resulting orange mixture was heated to 60° C. for 1 h. The reactionwas cooled to room temperature and then crushed ice (˜100 mL) was added,followed by water to a total volume of ˜400 mL causing a yellow solid tocrystallize from solution. The slurry was stirred for a few minutes andthen collected by vacuum filtration and the resulting initially yellowsolid was rinsed with additional water (˜100 mL) until all of the yellowcolor was rinsed into the filtrate giving a near white solid in thefunnel. Partially air-dried solid in funnel then transferred to a flaskand further dried under vacuum overnight to afford 10.5 g (98%) of ayellow solid as the desired product. LC retention time 0.83 [J].

Step 2

Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in acold solution of ammonia in methanol (7N, 250 mL) and conc. aqueousammonium hydroxide (100 mL) was added. The flask was sealed and theresulting solution was allowed to gently stir at room temperatureovernight (˜17 h). The reaction mixture was concentrated on the rotovapusing a slightly warm water bath to yield an aqueous slurry of theproduct. This slurry was diluted with additional water (˜300 mL) and wassonicated briefly then the solid was collected by vacuum filtration andthe resulting yellow solid was rinsed with additional water (˜100 mL).The solid was air dried in the funnel for several hours then undervacuum to afford 7.12 g of a yellow solid as the pure product. A secondcrop of product was obtained by extracting the filtrate with EtOAc(3×100 mL) followed by washing the extracts with brine, drying overanhydrous sodium sulfate, decanting and concentration under vacuum toafford 1.67 g of additional product as a yellow solid (86% overallcombined yield). LC retention time 0.58 [J]. MS(E⁺) m/z: 197 (MH⁺).

Step 3

2-Methoxy-3-nitrobenzamide (7.1 g, 36.2 mmol) was slurried in dimethylformamide dimethyl acetal (48.5 mL, 362 mmol) and the mixture was heatedto 95° C. giving a clear, pale yellow solution. After heating for ˜30min at this temp the reaction was cooled and was concentrated on therotovap and the resulting yellow oil was azeotroped twice with1,2-dichloroethane (40 mL portions) to ensure complete removal of anyresidual dimethyl formamide dimethyl acetal. The crude oil thus obtainedwas immediately dissolved in 35 mL of ethanol and was immediately usedin the following step.

In a separate flask was prepared a mixture of ethanol (150 mL) andacetic acid (AcOH, 35 mL) and the resulting solution was cooled in anice bath. Once cooled, hydrazine hydrate (17.59 mL, 362 mmol) was addeddropwise. At this time, the solution containing the crude dimethylformamide dimethyl acetal adduct as prepared above was transferreddropwise over ˜15 min by cannula into the previously preparedwell-stirred ice-cold mixture containing the hydrazine. During theaddition, a pale yellow solid formed in the solution. After the additionwas complete, the resulting cloudy yellow mixture was allowed to warm toroom temperature and stir for ˜4 h. The reaction mixture at this timewas concentrated on the rotovap to remove some of the ethanol, dilutedwith additional water and filtered to collect the solid. The solid waswashed with additional portions of water, air dried in the funnel thenunder vacuum to afford 5.5 g (69%) of a pale yellow solid as the desiredproduct. LC retention time 0.62 [J]. MS(E⁺) m/z: 221 (MH⁺).

Step 4

To a solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole (1.76 g,7.99 mmol), diisopropylethylamine (DIPEA, Hunig's base, 1.954 mL, 11.19mmol) and N,N′-dimethylaminopyridine (DMAP, 0.098 g, 0.799 mmol) indichloromethane (25 mL) at room temperature was added2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 1.701 mL, 9.59 mmol)and the reaction mixture was stirred at room temperature for 3 h.Mixture was then concentrated to remove the solvent, water was added andthe mixture was extracted with EtOAc (100 mL×4). The combined extractswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated to afford a tan semi-solid as the crude product. Thismaterial was purified by silica gel chromatography (hex/EtOAc; 40 gcolumn) to afford fractions containing the major product. Thesefractions were concentrated to afford 1.26 g (45%) of a clear oil as thedesired product (1.26 g, 3.60 mmol, 45% yield) as an apparent 2:3mixture of regioisomers. HPLC RT=3.44 and 3.53 min. LCMS (m+1)=351.Major isomer: ¹H NMR (400 MHz, chloroform-d) δ 8.34 (s, 2H), 8.25 (dd,J=7.8, 1.7 Hz, 2H), 7.82 (dd, J=8.0, 1.7 Hz, 2H), 7.31 (t, J=8.0 Hz,2H), 5.59 (s, 4H), 3.96 (s, 7H), 3.76-3.71 (m, 5H), 1.02-0.92 (m, 4H),0.01 (s, 9H).

Step 5

To a slurry of3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole(1.26 g, 3.60 mmol) in EtOH (50 mL) was added Pd/C (10% on carbon)(0.115 g, 0.108 mmol). The flask was evacuated and supplied withhydrogen gas from a balloon for 4 hours. At this time, the balloon wasremoved and reaction was flushed with nitrogen, then filtered through apad of CELITE® to remove the catalyst and the resulting clear colorlessfiltrate was concentrated to afford 1.12 g (97%) of the product as aclear oil which solidified on standing. HPLC and LCMS analysis indicatedan ˜2:3 mixture of regioisomers. HPLC Peak RT=2.70 min (major) and 3.01min (minor).

Step 1

A solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole from Step 3of Preparation 9 (2.23 g, 10.13 mmol) in DMF (20 mL) was treated withpotassium carbonate (4.20 g, 30.4 mmol). After cooling the resultingmixture in an ice bath, a solution of iodomethane (0.855 mL, 13.67 mmol)in DMF (5 mL) was slowly added dropwise by syringe over 2 min. After theaddition was complete, the ice bath was removed and the reaction mixturewas allowed to warm to rt. After stirring at room temperature for ˜4 h,LCMS analysis indicated complete and clean conversion to theregioisomeric mixture of products in ˜2:1 ratio, respectively. Thereaction was cooled in an ice bath and was diluted with water (˜50 mL)and the solution was extracted with EtOAc (3×40 mL) and the combinedextracts were washed with 10% aq. LiCl (2×20 mL), water (20 mL) thenbrine before concentrating to afford 2.17 g (91%) of a yellow oil as thecrude product which solidified to a yellow solid upon standing. Thiscrude material was combined with another batch of additional crudeproduct (˜0.45 g) from a previous similar reaction and the material waspurified by supercritical fluid chromatograph (SFC) to resolve theisomers (Conditions: column=chiral IC 3×25 cm, 5 μm; column temp.=35°C.; flow rate=200 mL/min; mobile phase=CO₂/MeOH=80/20; injectionprogram=stacked (2.3 min/cycle), 2.5 ml/per injection; sampler conc.(mg/mL): 60 mg/mL; detector wavelength=220 nm) to afford 1.87 g (65%) ofthe major isomer as a pale yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ8.50 (s, 1H), 8.11 (dd, J=7.9, 1.8 Hz, 1H), 7.85 (dd, J=8.1, 1.8 Hz,1H), 7.38 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H). LC retentiontime 0.74 [J]. MS(E⁺) m/z: 235 (MH⁺).

Step 2

A solution of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole(1.87 g, 7.98 mmol) in EtOH (50 mL) was sparged with nitrogen for a fewminutes before adding 5% Pd—C (0.850 g, 0.399 mmol) followed by spargingwith hydrogen from a balloon for a few minutes then allowing the mixtureto stir under a balloon of hydrogen for 1.5 h at rt. The mixture wasthen sparged with nitrogen to deactivate the catalyst and the mixturewas filtered through a pad of CELITE® washing with additional amounts ofEtOH and the resulting clear, colorless filtrate containing the productwas concentrated under vacuum to afford a colorless oil. This materialwas azeotroped with two portions of dry toluene (˜25 mL each) to affordan off-white solid which was dried further under vacuum to afford 1.5 g(92%) of a free-flowing white solid as the pure product. ¹H NMR (400MHz, chloroform-d) δ 8.09 (s, 1H), 7.35 (dd, J=7.8, 1.7 Hz, 1H), 7.00(t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 1.7 Hz, 1H), 4.00 (s, 3H), 3.94 (br.s., 2H), 3.78 (s, 3H). LC retention time 0.44 [J]. MS(E⁺) m/z: 205(MH⁺).

Step 1

Prepared using the procedure previously described in Step 3 ofPreparation 9 by replacing dimethyl formamide dimethyl acetal with1,1-dimethoxy-N,N-dimethylethanamine to afford 1.32 g (74%) of theproduct, 3-(2-methoxy-3-nitrophenyl)-5-methyl-4H-1,2,4-triazole as adark solid. ¹H NMR (400 MHz, chloroform-d) δ 8.45 (dd, J=7.9, 1.5 Hz,1H), 7.93 (dd, J=8.1, 1.8 Hz, 1H), 7.42-7.33 (m, 1H), 3.97 (s, 3H), 2.53(s, 3H). LC retention time 1.58 [A]. MS(E⁺) m/z: 235 (MH⁺).

Step 2

Prepared using the procedure previously described in Step 5 ofPreparation 9 to afford 0.97 g (86%) of the product as a clear oil whichsolidified upon standing (not characterized)

Step 1

Sodium azide (497 mg, 7.65 mmol) was suspended in acetonitrile (5.0 mL)at room temperature, silicon tetrachloride (0.322 mL, 2.80 mmol) wasadded and the reaction mixture became milky white. The amide substrate(500 mg, 2.55 mmol) was added as solid at this time and the mixture washeated under nitrogen at 75° C. for 4 h. The reaction was then allowedto cool to room temperature and stirred overnight. Water (50 mL) wasadded and after sonication, the solid was collected by filtration,rinsed with water and dried on the filter to afford 556 mg (99%) of ayellow solid as the desired product. LC retention time 0.65 [J]. MS(E⁺)m/z: 222 (MH⁺).

Step 2

To a solution of 5-(2-methoxy-3-nitrophenyl)-2H-tetrazole (535 mg, 2.419mmol) in DMF (1.0 mL) was added iodomethane (0.303 mL, 4.84 mmol) andK₂CO₃ and the resulting mixture was stirred at room temperature for 3 h.The reaction was cooled in an ice bath and was diluted with water (˜100mL) and the solution was extracted with EtOAc (3×100 mL). The combinedextracts were washed with 10% aq. LiCl (2×40 mL), water (40 mL) thenbrine, then dried over sodium sulfate before concentrating to afford 0.6g of a yellow oil as the crude product as a ˜3:1 mixture ofregioisomers. This material was purified by SFC to resolve theregioisomers. The major regioisomer was the first eluted product(Conditions: column=cell 45×25 cm, 5 μm; column temp.=40° C.; flowrate=250 mL/min; mobile phase=CO₂/MeOH=70/30; injection program=stacked(2.5 min/cycle), 1.0 ml/per injection; sampler conc. (mg/mL)=60;detector wavelength=220 nm).

Major regioisomer (372 mg, 65% yield). ¹H NMR (400 MHz, chloroform-d) δ8.35-8.26 (m, 1H), 7.98-7.85 (m, 1H), 7.44-7.32 (m, 1H), 4.48 (s, 3H),3.99 (s, 3H). LC retention time 0.79 [J]. MS(E⁺) m/z: 236 (MH⁺).

Minor regioisomer (139 mg, 24% yield). ¹H NMR (400 MHz, chloroform-d) δ8.11 (dd, J=8.3, 1.7 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 7.46 (t,J=8.0 Hz, 1H), 4.05 (s, 3H), 3.68 (s, 3H). LC retention time 0.70[J].MS(E⁺) m/z: 236 (MH⁺).

Step 3

A solution of 5-(2-methoxy-3-nitrophenyl)-2-methyl-2H-tetrazole (0.37 g,1.573 mmol) in EtOH (10 mL) was sparged with nitrogen for a few minutesbefore adding 5% Pd—C (10% on Carbon) (0.084 g, 0.079 mmol) followed bysparging with hydrogen from a balloon for a few minutes then lettingmixture stir under a balloon of hydrogen for 1.5 h at room temperature.The mixture was then sparged with nitrogen to deactivate the catalystand the mixture was filtered through Millipore 45μ filter washing withadditional amounts of EtOH and the resulting clear, colorless filtratecontaining the product was concentrated under vacuum to afford acolorless oil. After further concentrating under vacuum, a solid wasobtained and this material was azeotroped with two portions of drytoluene (˜25 mL each), then further dried under vacuum to afford 0.286 g(89%) of a colorless oil as the pure product. ¹H NMR (400 MHz,chloroform-d) δ 7.41 (dd, J=7.7, 1.5 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H),6.89 (dd, J=7.8, 1.7 Hz, 1H), 4.44 (s, 3H), 3.98 (br. s., 2H), 3.81 (s,3H). LC retention time 0.54 [J]. MS(E⁺) m/z: 206 (MH⁺).

The corresponding minor regioisomer was reduced in a similar mannerproviding 119 mg (98%) of the corresponding aniline. LC retention time0.52 [J]. MS(E⁺) m/z: 206 (MH⁺).

Step 1

A mixture of 2-hydroxy-3-nitrobenzoic acid (1.0 g, 5.46 mmol),iodomethane (1.02 mL, 16.4 mmol) and potassium carbonate (3.02 g, 21.8mmol) in DMF (25 mL) was heated at 50° C. overnight. The reactionmixture was cooled to room temperature, then diluted with ice-water [100mL] with vigorous stirring, then filtered. The solid product was driedto give 0.962 g white solid product (83% yield). ¹H NMR (400 MHz,DMSO-d6) □δ 8.12 (dd, J=8.1, 1.5 Hz, 1H), 8.03 (dd, J=7.8, 1.5 Hz, 1H),7.44 (t, J=7.9 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H). LC retention time2.22 [A]. MS(E⁺) m/z: 212 (MH⁺).

Step 2

A stirred solution of methyl 2-methoxy-3-nitrobenzoate (0.962 g, 4.56mmol) in methanol (10 mL) was heated to 75° C. 1.0 N (aq.) sodiumhydroxide (9.57 mL, 9.57 mmol) was added dropwise and the reactionmixture heated at 75° C. for fifteen minutes. The reaction mixture wascooled to room temperature and concentrated to remove the methanolsolvent. The residue was acidified with 1N (aq.) HCl solution to pH˜1,stirred and filtered. The solid residue was air-dried to give 0.841 gwhite solid product (94% yield). ¹H NMR (400 MHz, DMSO-d₆) □δ 8.06 (dd,J=7.9, 1.5 Hz, 1H), 8.01 (dd, J=7.7, 1.5 Hz, 1H), 7.40 (t, J=7.9 Hz,1H), 3.89 (s, 3H). LC retention time 1.78 min [A].

Step 3

A mixture of 2-methoxy-3-nitrobenzoic acid (0.841 g, 4.27 mmol),tert-butyl carbazate (0.677 g, 5.12 mmol),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (1.52 g, 5.12 mmol) and N,N-diisopropylethylamine (0.892 ml, 5.12mmol) in DMF (10 ml) was stirred at room temperature for overnight. Thereaction mixture was concentrated under vacuum. The residue waspartitioned between ethyl acetate and water. The ethyl acetate extractwas separated and concentrated. The residue was triturated with coldwater. A white solid precipitated. The mixture was filtered. The solidresidue was air-dried to give 1.12 g off-white solid product (84%yield). LC retention time 0.77 [J]. MS(E⁺) m/z: 312 (MH⁺).

Step 4

Trifluoroacetic acid (0.787 mL, 10.60 mmol) was added to a stirredsolution of tert-butyl 2-(2-methoxy-3-nitrobenzoyl) hydrazinecarboxylate(1.10 g, 3.53 mmol) in dichloromethane (10 mL) at room temperature. Thereaction mixture was stirred for one hour at room temperature. Thereaction mixture was concentrated under vacuum with repeated additionsof dichloromethane to evaporate of residual TFA to give 0.730 g tansolid product. (Yield 98%). LC retention time 0.70 [A]. MS(E⁺) m/z: 212(MH⁺).

Step 5

A stirred mixture of 2-methoxy-3-nitrobenzohydrazide (0.050 g, 0.237mmol) and trimethylorthoacetate (0.603 ml, 4.74 mmol) was heated at 105°C. for overnight. LC-MS indicated complete conversion to the desiredproduct. The reaction mixture was concentrated under high vacuum toremove excess reactant/solvent. The crude residue partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The ethylacetate extract was dried over sodium sulfate and concentrated to give0.049 g product as a viscous tan liquid (yield 88%). LC retention time0.75 [J]. MS(E⁺) m/z: 236 (MH⁺).

Step 6

A mixture of 2-(2-methoxy-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole(0.510 g, 2.168 mmol), zinc (1.418 g, 21.68 mmol) and ammonium chloride(1.160 g, 21.68 mmol) in methanol (25 mL) and THF (8.33 mL) was stirredat room temperature for 2 hours. The reaction mixture was diluted withethyl acetate and filtered through a CELITE® pad. The filtrate wasconcentrated under vacuum. The residue was dissolved in 100 mL ethylacetate and washed with water and brine, filtered, dried andconcentrated to give 0.412 g product as a tan solid (yield 93%). LCretention time 0.58 [J]. MS(E⁺) m/z: 206 (MH⁺).

Step 1

To a stirred solution of 2-methoxy-3-nitrobenzoic acid (850 mg, 4.31mmol) in DMF (9 mL), acetohydrazide (639 mg, 8.62 mmol),diisopropylethylamine (1.506 mL, 8.62 mmol) and BOP (1907 mg, 4.31 mmol)were added. The reaction mixture was stirred at room temperature for 2hours and then water was added to crash out the crude product. The solidwas filtered off, washed with water and then with petroleum ether togive N′-acetyl-2-methoxy-3-nitrobenzohydrazide (750 mg, 67% yield). ¹HNMR (400 MHz, DMSO-d₆) □δ 10.31 (s, 1H), 10.04 (s, 1H), 8.01 (dd, J=8.0,1.6 Hz, 1H), 7.72 (dd, J=8.0, 1.6 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 3.93(s, 3H), 1.92 (s, 3H).

Step 2

To a solution of N′-acetyl-2-methoxy-3-nitrobenzohydrazide (500 mg,1.975 mmol) in dioxane (20 mL) was added Lawesson's reagent (2.00 g,4.94 mmol) and the reaction was heated to 110° C. for 12 hours. Thereaction was then cooled to room temperature and concentrated andpartitioned between water and ethyl acetate. The two layers wereseparated and the aqueous layer extracted three times with ethylacetate. The combined organic layers were washed with 10% sodiumbicarbonate solution followed by brine. The organic layer was then driedover sodium sulfate, filtered, concentrated and purified by silica gelchromatography to provide2-(2-methoxy-3-nitrophenyl)-5-methyl-1,3,4-thiadiazole (400 mg, 60%yield). LC retention time 1.92 [R]. MS(E⁺) m/z: 252 (MH⁺).

Step 3

To a stirred solution of2-(2-methoxy-3-nitrophenyl)-5-methyl-1,3,4-thiadiazole (50 mg, 0.199mmol) in methanol (1 mL), 10% palladium on carbon (212 mg, 0.199 mmol)was added and kept under hydrogen atmosphere of 10 psi at roomtemperature for 2 hours. The reaction mixture was filtered throughCELITE® and the organic layer was concentrated under vacuum to dryness.The crude residue was purified by automated chromatography to get thedesired 2-methoxy-3-(5-methyl-1,3,4-thiadiazol-2-yl)aniline (35 mg, 43%yield). LC retention time 1.63 [R]. MS(E⁺) m/z: 222 (MH⁺).

Example 52

Step 1

To a solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline(10.26 g, 50.2 mmol) and Int8 (10.5 g, 50.2 mmol) in THF (120 mL) wasadded lithium bis(trimethylsilyl)amide (LiHMDS, 1M in THF, 151 mL, 151mmol) in a dropwise manner using a pressure equalized addition funnel.The reaction was run for 10 minutes after the completion of the additionand then quenched with HCl (1M aq., 126 mL, 126 mmol). The reaction wasconcentrated on a rotary evaporator until the majority of the THF wasremoved and a precipitate prevailed throughout the vessel. Water (˜500mL) was then added and the slurry sonicated for 5 minutes and stirredfor 15 min. The solid was filtered off, rinsing with water and then airdried for 30 minutes. The powder was collected and dissolved indichloromethane. The organic layer was washed with water and brine andthen dried over sodium sulfate, filtered and concentrated to provide theproduct (12.5 g, 66% yield) (carried on as is). ¹H NMR (400 MHz,DMSO-d₆) δ 11.11 (s, 1H), 9.36 (s, 1H), 8.56 (s, 1H), 7.72 (dd, J=7.8,1.6 Hz, 1H), 7.60 (dd, J=7.9, 1.5 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.19(s, 1H), 3.95 (s, 3H), 3.72 (s, 3H). LC retention time 1.18 [E]. MS(E⁺⁾m/z: 377 (MH⁺).

Step 2

Int13 (2.32 g, 6.16 mmol) and cyclopropanecarboxamide (1.048 g, 12.31mmol) were dissolved in dioxane (62 mL) and Pd₂(dba)₃ (564 mg, 0.616mmol), Xantphos (534 mg, 0.924 mmol) and cesium carbonate (4.01 g, 12.3mmol) were added. The vessel was evacuated three times (backfilling withnitrogen) and then sealed and heated to 130° C. for 140 minutes. Thereaction was filtered through CELITE® (eluting with ethyl acetate) andconcentrated (on smaller scale this material could then be purifiedusing preparative HPLC). The crude product was adsorbed onto CELITE®using dichloromethane, dried and purified using automated chromatography(100% EtOAc) to provide example 52 (1.22 g, 46% yield). ¹H NMR (500 MHz,chloroform-d) δ 10.99 (s, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (d,J=0.5 Hz, 2H), 7.81 (dd, J=7.9, 1.7 Hz, 1H), 7.51 (dd, J=7.9, 1.4 Hz,1H), 7.33-7.20 (m, 1H), 4.01 (d, J=0.3 Hz, 3H), 3.82 (s, 3H), 1.73-1.60(m, 1H), 1.16-1.06 (m, 2H), 0.97-0.84 (m, 2H). LC retention time 6.84[N]. MS(E⁺) m/z: 426 (MH⁺).

Example 53

To a homogeneous solution of Example 52 (50 mg, 0.12 mmol) indichloromethane (3 mL) was added HCl (1M aq., 0.13 mL, 0.13 mmol)resulting in the solution turning yellow. The homogenous solution wasconcentrated down and then re-concentrated from dichloromethane twice toremove residual water, resulting in a white powder. The powder wassuspended in dichloromethane and sonicated for 15 minutes, the powderwas then collected via filtration, rinsing with dichloromethane toprovide the corresponding HCl salt (38 mg, 70% yield). ¹H NMR (500 MHz,chloroform-d) δ 12.02 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.01 (dd,J=7.9, 1.5 Hz, 1H), 7.57 (br. s., 1H), 7.52-7.46 (m, 1H), 7.36 (t, J=7.9Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 2.05-1.95 (m, 1H), 1.16-1.09 (m,2H), 1.03 (dd, J=7.4, 3.6 Hz, 2H). LC retention time 0.62 [J]. MS(E⁺)m/z: 426 (MH⁺).

Compare to NMR of parent free base: ¹H NMR (500 MHz, chloroform-d) δ10.99 (s, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=0.5 Hz, 2H), 7.81(dd, J=7.9, 1.7 Hz, 1H), 7.51 (dd, J=7.9, 1.4 Hz, 1H), 7.33-7.20 (m,1H), 4.01 (d, J=0.3 Hz, 3H), 3.82 (s, 3H), 1.73-1.60 (m, 1H), 1.16-1.06(m, 2H), 0.97-0.84 (m, 2H).

The following Examples were prepared in a similar manner to the productof Example 52. The aniline used in each case was prepared following thepreparation number, or in a manner similar to it, as denoted for eachentry:

Example Preparation Rt (min) m/z No. No. R¹ R² [Method] [M + H]⁺  54 4

1.44 [E] 425  55 4

1.82 [E] 466  56 10

1.49 [E] 467  57 4

1.44 [E] 463  58 4

1.63 [E] 434  59 4

1.76 [E] 466  60 10

1.28 [E] 452  61 4

1.57 [E] 434  62 10

1.58 [E] 508  63 4

1.42 [E] 425  64 5

1.45 [E] 411  65 5

1.58 [E] 420  66 5

1.86 [E] 452  67 4

1.18 [E] 425  68 10

1.26[E] 464  69 4

2.29 [A] 437  70 4

2.07 [A] 423  71 4

2.15 [A] 450  72 4

1.86 [A] 422  73 4

1.86 [E] 451  74 4

2.35 [A] 450  75 4

2.35 [A] 423  76 10

1.29 [E] 435  77 4

1.76 [A] 449  78 4

2.11 [A] 423  79 4

1.35 [E] 450  80 *CD₃ replaced with CH₃* 4

11.14 [O] 462  81 *CD₃ replaced with CH₃* 4

6.64 [P] 448  82 4

2.42 [A] 437  83 4

2.36 [A] 464  84 10

1.09 [E] 479  85 4

1.41 [E] 451  86 4

2.65 [A] 423  87 10

1.14 [E] 494  88 10

1.27 [E] 466  89 4

1.43 [E] 450  90 *CD₃ replaced with CH₃* 4

7.04 [P] 439  91 4

2.20 [A] 432  92 4

2.29 [A] 449  93 4

1.44 [E] 451  94 10

1.07 [E] 436  95 4

1.67 [E] 442  96 4

1.38 [E] 432  97 4

1.71 [E] 480  98 10

1.47 [E] 494  99 10

1.05 [E] 578 100 4

1.74 [E] 468 101 4

1.70 [E] 442 102 10

1.05 [E] 465 103 10

1.04 [E] 450 104 4

1.68 [E] 468 105 4

1.44 [E] 428 106 4

1.76 [E] 469 107 4

1.43 [E] 454 108 10

1.19 [E] 464 109 10

1.14 [E] 450 110 10

1.09 [E] 465 111 4

2.16 [A] 435 112 4

2.03 [A] 433 113 4

2.18 [A] 447 114 10

1.08 [E] 494 115 10

1.23 [E] 478 116 4

2.62 [A] 441 117 4

1.83 [E] 451 118 4

1.94 [A] 433 119 4

2.03 [A] 447 120 10

1.16 [E] 493 121 4

2.09 [A] 461 122 4

2.06 [A] 447 123 4

1.96 [A] 433 124 4

2.03 [E] 483 125 commercial source

1.45 [E] 345 126 4

1.54 [E] 428 127 10

1.53 [E] 479 128 10

1.45 [E] 463 129 4

1.89 [E] 469 130 4

1.51 [E] 466 131 4

1.53 [E] 454 132 4

1.68 [E] 437 133 10

1.32 [E] 465 134 10

1.30 [E] 533 135 10

1.30 [E] 479 136 6

1.42 [E] 426 137 6

1.43 [E] 464 138 6

1.24 [E] 426 139 7

1.66 [E] 369 140 8

1.37 [E] 465 141 11

1.11 [E] 426 142 11

1.43 [E] 467 143 12

1.26 [E] 427 144 12

0.63 [J] 465 145 12

1.37 [E] 436 146 12

1.30 [E] 427 147 12

1.43 [E] 436 148 11

1.09 [E] 452 149 13

1.29 [E] 427 150 13

1.63 [E] 468 151 13

1.34 [E] 436 152 13

1.31 [E] 453 153 13

1.19 [E] 465 154 *CD₃ replaced with CH₃* 14

1.92 [R] 440 155 *CD₃ replaced with CH₃* 14

2.01 [R] 449 156 *CD₃ replaced with CH₃* 13

2.04 [R] 433 157 4

1.50 [E] 481 158 4

2.02 [A] 447 159 4

1.19 [E] 425 160 4

1.53 [E] 442 161 4

1.51 [E] 468

Step 1

To a solution of Int8 (200 mg, 0.957 mmol) and ethyl3-amino-2-methoxybenzoate (187 mg, 0.957 mmol) in THF (9 mL) at roomtemperature was added dropwise over 1 minute LiHMDS (1M in THF, 2.392mL, 2.392 mmol). The resulting solution was stirred at room temperaturefor 1 hr. The reaction mixture was quenched with saturated ammoniumchloride solution (2 ml). The mixture was partitioned between EtOAc (40ml) and saturated ammonium chloride solution (40 ml). The organic layerwas washed with brine (40 ml), dried (Na₂SO₄) and concentrated to afforda solid residue that was purified on a 12 gm ISCO silica gel cartridge,eluting with a 0-100% EtOAc/hex gradient. The pure fractions wereconcentrated to afford ethyl3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(301 mg, 0.818 mmol, 86% yield) as an tan solid. LC retention time 2.28minutes [Q]. MS(ESI⁺) m/z: 368.2/370.2 (MH⁺), chlorine pattern. ¹H NMR(400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.37 (s, 1H), 7.76 (dd, J=7.9, 1.3Hz, 1H), 7.57 (dd, J=7.9, 1.5 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.20 (s,1H), 4.33 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).

Step 2 A mixture of ethyl3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(240 mg, 0.653 mmol), cyclopropanecarboxamide (111 mg, 1.305 mmol),Pd₂(dba)₃ (59.8 mg, 0.065 mmol), Xantphos (76 mg, 0.131 mmol) and Cs₂CO₃(850 mg, 2.61 mmol) in dioxane (5 mL) was degassed by bubbling nitrogenthrough the mixture for 5 minutes. The reaction vessel was sealed andheated to 130° C. for 8 hr. After cooling to room temperature, thereaction mixture was partitioned between EtOAc (50 ml) and water (50ml). The aqueous layer was extracted with EtOAc (30 ml) and the combinedorganics were dried (Na₂SO₄) and concentrated to afford a semisolid thatwas purified on a 24 gm ISCO silica gel cartridge, eluting with a 0-100%EtOAc/hex gradient. The pure fractions were concentrated to afford ethyl3-((6-(cyclopropanecarboxamido)-3-(tridueteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(115 mg, 0.276 mmol, 42.3% yield) as a tan solid. Used as is. LCretention time 2.02 minutes [Q]. MS(ESI⁺) m/z: 417.5 (MH⁺).

Step 3

A mixture of ethyl3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(114 mg, 0.274 mmol) and NaOH, 1M (1.369 mL, 1.369 mmol) in MeOH (2.5mL) and THF (1 mL) was stirred at room temperature for 3.5 hr. Thereaction was diluted with water (10 ml) and the pH was adjusted to ˜1with 1N HCl. The mixture was extracted with EtOAc (30 ml). The organiclayer was washed with brine (30 ml), dried (MgSO₄) and concentrated toafford3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoicacid (74 mg, 0.191 mmol, 69.6% yield) as a yellow solid. Used as is. LCretention time 1.55 minutes [Q]. MS(ESI⁺) m/z: 389.3 (MH⁺).

Step 4

A mixture of3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoicacid (73 mg, 0.188 mmol), hydroxybenzotriazole (HOBt) (34.5 mg, 0.226mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (43.2 mg,0.226 mmol) in DMF (1.5 mL) was stirred at room temperature for 30minutes. At this time, (Z)—N′-hydroxyacetimidamide (13.92 mg, 0.188mmol) was added and stirring was continued at room temperature for 1.5hr. The reaction mixture was partitioned between EtOAc (20 ml) andsaturated sodium bicarbonate solution (20 ml). The organic layer waswashed with water (2×20 ml) and brine (20 ml). After drying (Na₂SO₄) andfiltration the organic layer was concentrated to afford(Z)-4-((3-((((1-aminoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(57 mg, 0.128 mmol, 68.2% yield) as a light yellow oil. Used as is. LCretention time 1.65 minutes [Q]. MS(ESI⁺) m/z: 445.4 (MH⁺).

Example 162

To a solution of(Z)-4-((3-((((1-aminoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(51 mg, 0.115 mmol) in ethanol (3 mL) was added sodium acetate,trihydrate (39.1 mg, 0.287 mmol) as a solution in water (0.5 mL) and theresulting mixture was heated to 80° C. for 20 hours. After cooling toroom temperature, the reaction mixture was filtered and the resultingsolid was washed with water and EtOH. The solid was triturated with EtOHwith heating and sonication and overnight stirring. Filtration anddrying afforded6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(10 mg, 0.022 mmol, 18.80% yield) as a light yellow solid. LC retentiontime 2.05 minutes [Q]. MS(ESI⁺⁾ m/z: 427.4 (MH⁺). ¹H NMR (400 MHz,DMSO-d₆) δ 11.36 (s, 1H), 11.06 (s, 1H), 9.17 (s, 1H), 8.13 (s, 1H),7.79 (ddd, J=17.6, 8.0, 1.4 Hz, 2H), 7.42 (t, J=7.9 Hz, 1H), 3.78 (s,3H), 2.45 (s, 3H), 2.16-2.02 (m, 1H), 0.89-0.68 (m, 4H).

Step 1

A mixture of Int14 (120 mg, 0.326 mmol), pyridin-2-amine (61.4 mg, 0.653mmol), Pd₂(dba)₃ (29.9 mg, 0.033 mmol), Xantphos (37.8 mg, 0.065 mmol)and Cs₂CO₃ (425 mg, 1.305 mmol) in dioxane (2.5 mL) was degassed bybubbling nitrogen through the mixture for 5 minutes. The reaction vesselwas sealed and heated to 130° C. for 8 hr. After cooling to roomtemperature, the reaction mixture was partitioned between EtOAc (50 ml)and water (50 ml). The aqueous layer was extracted with EtOAc (30 ml)and the combined organics were dried (Na₂SO₄) and concentrated to affordethyl2-methoxy-3-((3-(trideuteromethylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)benzoate(139 mg, 0.327 mmol, 99% yield) a yellow solid. Attempts to purify wereunsuccessful and the crude product mixture was taken on as is. LCretention time 2.13 minutes [Q]. MS(ESI⁺) m/z: 426.4 (MH⁺).

Step 2

A mixture of Int18 (92 mg, 0.232 mmol) and NaOH, 1N NaOH (1.634 mL,1.634 mmol) in MeOH (3 mL) and THF (1 mL) was stirred at roomtemperature for 22 hr. The organic solvents were removed in vacuo andthe residue was diluted with 20 ml of water the pH was adjusted to ˜1with 1N HCl and the resulting mixture was extracted with EtOAc (2×50 ml)and EtOAc:THF, 1:1 (50 ml). After drying (Na₂SO₄) and filtration theorganic layer was concentrated to afford Int19 (92 mg, 0.232 mmol, 70.9%yield) as a yellow solid. Used as is. LC retention time 1.88 minutes[Q]. MS(ESI⁺) m/z: 398.3 (MH⁺).

Step 3

A mixture of2-methoxy-3-((3-(trideuteromethylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)benzoicacid (90 mg, 0.226 mmol), HOBt (41.6 mg, 0.272 mmol) and EDC (52.1 mg,0.272 mmol) in DMF (2 mL) was stirred at room temperature for 30minutes. At this time, (Z)—N′-hydroxyacetimidamide (16.78 mg, 0.226mmol) was added and stirring was continued at room temperature for 18hr. The reaction mixture was partitioned between EtOAc (20 ml) andsaturated sodium bicarbonate solution (20 ml). The organic layer waswashed with 10% LiCl solution (2×20 ml) and brine (20 ml). After drying(Na₂SO₄) and filtration the organic layer was concentrated to affordInt20 (69 mg, 0.152 mmol, 67.2% yield) as a light yellow solid. Used asis. LC retention time 1.88 minutes [Q]. MS(ESI⁺⁾ m/z: 454.4 (MH⁺).

Example 163

To a solution of Int20 (68 mg, 0.150 mmol) in ethanol (3 mL) was addedsodium acetate trihydrate (51.1 mg, 0.375 mmol) as a solution in water(0.5 mL) and the resulting mixture was heated to 80° C. for 30 hr. Aftercooling to room temperature, the reaction mixture was filtered and thefilter cake was washed with water followed by EtOH. Drying afforded4-((2-methoxy-3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)amino)-N-trideutero-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(12 mg, 0.026 mmol, 17.55% yield) as a white solid. LC retention time2.23 minutes [Q]. MS(ESI⁺⁾m/z: 436.4 (MH⁺). ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 10.19 (s, 1H), 9.12 (s, 1H), 8.27-8.13 (m, 2H), 7.95-7.87(m, 1H), 7.79 (dd, J=7.9, 1.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.58 (d, J=8.4Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 6.93 (dd, J=6.4, 5.1 Hz, 1H), 3.82 (s,3H), 2.46 (s, 3H).

Example 164

Int19

To a solution of Int19 (40 mg, 0.1 mmol) and 2-methoxyethanamine (10.4mg, 0.128 mmol) in DMF (1 mL) was added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 45 mg, 0.10 mmol) and N,N′-diisopropylethylamine (0.064 mL, 0.37mmol). The reaction was stirred for 10 minutes and then filtered througha micropore filter and purified by preparative HPLC to provide 164 (4.4mg, 10.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.18 (s,1H), 9.10 (s, 1H), 8.37 (t, J=5.2 Hz, 1H), 8.25-8.15 (m, 2H), 7.73-7.65(m, 2H), 7.56 (d, J=7.9 Hz, 1H), 7.39-7.34 (m, 1H), 7.33-7.26 (m, 1H),6.96-6.90 (m, 1H), 3.74 (s, 3H), 3.53-3.42 (m, 4H), 3.29 (s, 3H). LCretention time 1.28 [E]. MS(E⁺) m/z: 455 (MH⁺).

The following Examples were prepared in a similar manner to the productof Example 164:

Example Rt (min) m/z No. R [Method] [M + H]⁺ 165

1.32 [E] 437 166

1.23 [E] 469 167

1.89 [E] 481 168

1.27 [E] 483 169

1.18 [E] 411 170

1.21 [E] 455 171

1.08 [E] 479

Example 172

Int21 (prepared in a similar manner to Example 164) (30 mg, 0.076 mmol)was slurried in N,N-dimethylformamide dimethyl acetal (DMF-DMA, 1.5 mL,11.2 mmol) and heated to 110° C. The reaction was run for 30 minutes andthen dried, at which point acetic acid (0.12 mL) and ethanol (0.6 mL)were added, providing a clear solution. To this solution was addedhydrazine hydrate (0.024 mL, 0.76 mmol) and the reaction was stirred for30 minutes. The solution was filtered and purified using preparativeHPLC to provide 172 (2.5 mg, 7.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.01 (s, 1H), 10.18 (s, 1H), 9.11 (s, 1H), 8.26-8.15 (m, 2H), 7.73-7.65(m, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.37 (br. s., 1H), 6.92 (dd, J=6.7, 5.5Hz, 1H), 3.71 (s, 3H). LC retention time 1.16 [E]. MS(E⁺) m/z: 421(MH⁺).

Step 1

Int 8 (311 mg, 1.486 mmol) and2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline(Preparation 9, 500 mg, 1.560 mmol) were dissolved in THF (2 mL) andLHMDS (1 M in THF) (3.71 mL, 3.71 mmol) was added dropwise by syringe atroom temperature over ˜5 minutes causing a slight exotherm. The reactionmixture was stirred at room temperature for 15 min whereupon LCMS showedreaction was complete and starting material had been consumed. Crushedice was added followed by saturated aqueous ammonium chloride until pH˜7 was obtained. The mixture was stirred for 30 min, then extracted withEtOAc (80 mL×3) and the combined organic extracts were washed withbrine, dried over sodium sulfate, filtered and concentrated to afford730 mg of tan solid as the desired product as a mixture of regioisomers.HPLC RT=3.67 and 3.78 min. MS(E⁺) m/z: 493 (MH⁺).

Step 2

A mixture of the SEM-protected substrate (420 mg, 0.852 mmol),cyclopropanecarboxamide (145 mg, 1.704 mmol), Xantphos (99 mg, 0.170mmol) and cesium carbonate (833 mg, 2.56 mmol) in dioxane (3 mL) wassparged with nitrogen for 5 minutes, then Pd₂(dba)₃ (54.9 mg, 0.06 mmol)was added and the reaction was placed into a preheated 130° C. heatingblock for 1 h. The reaction was cooled and was partitioned between EtOAcand water and the layers were separated. The aqueous portion wasextracted with EtOAc and the combined extracts were washed with water,brine, dried over sodium sulfate, filtered and concentrated to affordtan oil which was purified via silica gel chromatography (hex/EtOAc; 12g column) to afford 383 mg (83%) of a tan semi-solid as the desiredproduct as a mixture of regioisomers. HPLC RT=3.62 min. MS(E⁺⁾ m/z:542.6 (MH⁺).

Example 173

To solution of the substrate (383 mg, 0.707 mmol) in dichloromethane (2mL) was added TFA (1.089 mL, 14.14 mmol) and the mixture was allowed tostir overnight at room temperature then concentrated to remove the TFAand the resulting residue was partitioned between EtOAc and water. Thelayers were separated and the aqueous portion was extracted withadditional EtOAc and the combined organics were washed with aq. satsodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated to afford 290 mg of a tan semi-solid as Example 173. Aportion of this material was purified using preparative HPLC to providean analytical sample for testing. ¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (br.s., 1H), 10.98 (br. s., 1H), 9.16 (br. s., 1H), 8.22-8.01 (m, 2H),7.86-7.65 (m, 1H), 7.57 (br. s., 1H), 7.39-7.17 (m, 1H), 3.67 (br. s.,3H), 2.06 (d, J=4.9 Hz, 1H), 0.87-0.73 (m, 4H).). LC retention time 1.05[E]. MS(E⁺) m/z: 412 (MH⁺).

Example 174

To slurry of Example 173 (50 mg, 0.085 mmol) and potassium carbonate(47.0 mg, 0.340 mmol) in DMF (0.3 mL) at room temperature was addediodoethane (19.90 mg, 0.128 mmol) and the resulting mixture was allowedto stir at room temperature for 3 h. A mixture of two regioisomers wasseen; however, these were typically separable by preparative HPLC(exceptions noted in the table). Structural assignment was made byanalysis of ¹H NMR compared to compounds with known (by synthesis orcrystal structure) regiochemistry. The crude reaction mixture wasdiluted with DMSO and was subjected to purification by reverse-phaseHPLC to afford fractions containing the major product. Concentration anddrying under vacuum afforded 6.4 mg (17%) of a solid as Example 174. ¹HNMR (500 MHz, DMSO-d₆) □ δ 11.29 (s, 1H), 10.94 (s, 1H), 9.10 (s, 1H),8.58 (s, 1H), 8.12 (s, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.50 (d, J=6.7 Hz,1H), 7.26 (t, J=7.6 Hz, 1H), 4.26 (q, J=7.3 Hz, 2H), 3.70 (s, 3H), 2.04(d, J=4.9 Hz, 1H), 1.44 (t, J=7.3 Hz, 3H), 0.88-0.75 (m, 4H). LCretention time 1.30 [E]. MS(E⁺) m/z: 440 (MH⁺).

The following Examples were prepared using similar conditions asdescribed for the preparation of Example 173 and Example 174:

Example Rt (min) m/z No. R¹ R² [Method] [M + H]⁺ 175

1.21 [E] 458 176 (as a mixture of regioisomers)

1.08 [E] 1.12 [E] 476 177

1.38 [E] 449 178

1.30 [E] 435 179

1.18 [E] 426 180

1.53 [E] 467

Examples 181 and 182

Step 1

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(Preparation 2, 700 mg, 3.35 mmol) and2-methoxy-3-(5-methyl-4H-1,2,4-triazol-3-yl)aniline (Preparation 11, 752mg, 3.68 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide(1M in THF, 11.7 mL, 11.7 mmol) in a dropwise manner. The reaction wasstirred for 15 minutes and then quenched with 1N HCl to pH ˜2. The 10suspension was stirred for 1 hour at 0° C., filtered and rinsed withwater to afford the intermediate as a brown solid (832 mg, 66% yield).LC retention time 0.53 [J]. MS(E⁺) m/z: 377 (MH⁺).

Step 2

To a solution of the above intermediate (60 mg, 0.16 mmol) in DMF (0.5mL) was added potassium carbonate (22 mg, 0.16 mmol) followed byiodomethane (0.013 mL, 0.21 mmol) in 0.1 mL DMF. The reaction wasstirred at room temperature for 3 hours, filtered and concentrated.Regioisomers were not separated. ¹H NMR major regioisomer only (400 MHz,methanol-d₄) δ 7.75 (dd, J=7.7, 1.5 Hz, 1H), 7.57 (dd, J=7.9, 1.5 Hz,1H), 7.38-7.32 (m, 1H), 7.19 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 2.57(s, 3H).

Step 3

The mixture of regioisomers obtained from the above methylation (18 mg,0.046 mmol) were dissolved in dioxane (0.4 mL) along withcyclopropanecarboxamide (7.8 mg, 0.092 mmol), Xantphos (5.3 mg, 0.009mmol) and cesium carbonate (30 mg, 0.092 mmol). The suspension wassparged with nitrogen for 5 minutes and then Pd₂(dba)₃ (8.4 mg, 0.009mmol) was added, the vessel sealed, and then heated to 130° C. for 1hour. After cooling to room temperature the reaction was filtered,diluted with DMSO and purified using preparative HPLC (isolating the tworegioisomers separately).

181 (10.9 mg, 43% yield):

¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.96 (s, 1H), 9.12 (s, 1H),8.10 (s, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.26 (t,J=7.9 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.46 (s, 3H), 2.13-1.98 (m,1H), 0.86-0.78 (m, 4H). LC retention time 0.94 [E]. MS(E⁺) m/z: 440(MH⁺).

182 (1.9 mg, 7.4% yield):

¹H NMR (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.94 (s, 1H), 9.13 (s, 1H),8.08 (s, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.38-7.21 (m, 2H), 3.64 (s, 3H),3.42 (s, 3H), 2.29 (s, 3H), 2.06 (br. s., 1H), 0.88-0.72 (m, 4H). LCretention time 1.22 [E]. MS(E⁺) m/z: 440 (MH⁺).

The following Examples were prepared using similar conditions asdescribed for the preparation of Example 181 and Example 182:

Example Rt (min) m/z No. R¹ R² [Method] [M + H]⁺ 183

0.84 [E] 478 184

1.23 [E] 478

Step 1

To a slurry of 1H-pyrazole (10 g, 147 mmol) in water (150 mL) at roomtemperature was added NBS (26.1 g, 147 mmol) in one portion. Reactionbecame milky white and was allowed to stir at room temperature for ˜24h. The reaction mixture was extracted with EtOAc (2×100 mL). Thecombined EtOAc extracts were washed with aqueous Na₂S₂O₃ and brine thendried over Na₂SO₄, and concentrated under reduced pressure to afford alight tan oil as 21.5 g (100%) of as a light tan oil that solidifiedupon standing. HPLC Peak RT=0.87 min.

Step 2

To solution of 4-bromo-1H-pyrazole (21.6 g, 147 mmol) in dichloromethane(400 mL) was added a solution of HCl (4 N in dioxane) (2.204 mL, 8.82mmol) and ethoxyethene (12.72 g, 176 mmol). After 30 min, the reactionwas quenched with aqueous NaHCO₃ (30 mL), stirred at room temperaturefor 1 h, and the two layers were separated. The organic layer was washedwith water, dried over Na₂SO₄, and concentrated under reduced pressureto dryness to afford the crude product (28 g). This material waspurified by silica gel chromatography using a solvent gradient of EtOAcin hexanes to afford after concentration 13.2 g (41%) of the product asa clear oil. ¹H NMR (400 MHz, chloroform-d) δ 7.61 (s, 1H), 7.47 (s,1H), 5.48 (q, J=5.9 Hz, 1H), 3.53-3.41 (m, 1H), 3.35 (dq, J=9.5, 7.0 Hz,1H), 1.68-1.62 (m, 3H), 1.21-1.12 (m, 3H).

Step 3

To an oven-dried vial was charged a solution of isopropylmagnesium/lithium chloride solution (1.0 M in THF) (6.32 ml, 8.22 mmol)at room temperature, and to this solution was added4-bromo-1-(1-ethoxyethyl)-1H-pyrazole (1.00 g, 4.56 mmol) dropwise andthe resulting mixture was stirred at room temperature for ˜16 h. Theresulting solution was then cooled to −20° C. and2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.731 g, 10.95 mmol)was added via syringe and the resulting mixture was allowed to warm tort. After 2 h at room temperature, the reaction was quenched by additionof aq. sat. ammonium chloride (15 mL) causing a white precipitate toform. After diluting with additional water (˜20 mL), the mixture wasextracted with hexanes (140 mL×2) and the combined extracts were washedwith aq. sat. sodium bicarbonate, brine, then dried over sodium sulfate,filtered and concentrated to afford 1.20 g (99%) of the product as acolorless oil.

Step 4

To a reaction vial charged with 3-bromo-2-methoxyaniline (0.30 g, 1.485mmol) and1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.435 g, 1.633 mmol) in dioxane (2 ml) was added 2 M aqueous potassiumphosphate (1.485 ml, 2.97 mmol) and the resulting mixture wasdeoxygenated by bubbling argon through the mixture for ˜5 min.PdCl₂(dppf) (0.033 g, 0.045 mmol) was then added and the mixture washeated at 110° C. for 3 h. The reaction was cooled, diluted with EtOAc(100 mL), washed with water then brine and dried over sodium sulfate.The resulting dried solution was filtered and concentrated to afford ablack oil which was purified via silica gel flash column chromatographyusing a gradient elution of ethyl acetate in hexanes. Fractionscontaining the desired product were concentrated under vacuum to afford3-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-methoxyaniline (355 mg, 1.358mmol, 91% yield) as an oil which solidified upon standing. HPLC PeakRT=1.58 min. and MS (m+1)=262.1.

Step 5

Preparation as previously described in Example 52 to afford 530 mg (98%)of a tan solid as the product.

Step 6

Preparation as previously described in Example 52 to afford 390 mg (94%)of a solid as the product.

Example 185

To solution of the substrate (Preparation 18) (390 mg, 0.808 mmol) indioxane at room temperature was added concentrated aq. HCl (0.682 mL,8.08 mmol) and the resulting mixture was stirred for 1 h. The reactionwas then concentrated and the residue was treated with aq. sat. sodiumbicarbonate, stirred for 2 h, and the solid obtained was collected byfiltration and rinsed with water and dried to afford 320 mg (96%) of atan solid as Example 185. An analytically pure sample was prepared usingpreparative HPLC. ¹H NMR (500 MHz, DMSO-d₆) δ 13.07 (br. s., 1H), 11.25(s, 1H), 10.89 (s, 1H), 9.07 (s, 1H), 8.11 (s, 1H), 8.09-7.96 (m, 2H),7.46 (d, J=7.3 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.21-7.12 (m, 1H), 3.54(s, 3H), 2.08-1.97 (m, 1H), 0.89-0.73 (m, 4H). LC retention time 1.33[E]. m/z: 411 (MH⁺).

Example 186

To slurry of the substrate Example 185 (25 mg, 0.061 mmol) and1-bromo-2-fluoroethane (15.47 mg, 0.122 mmol) in DMF (0.3 mL) at roomtemperature was added 1-bromo-2-fluoroethane (15.47 mg, 0.122 mmol)stirred at room temperature for 3 h and 60° C. for an additional 3 h.The crude reaction mixture was diluted with DMSO and was subjected toreverse-phase HPLC to afford fractions containing the desired productwhich were concentrated under vacuum to afford 2.5 mg of Example 186. ¹HNMR (500 MHz, DMSO-d₆) δ 11.29 (s, 1H), 10.93 (s, 1H), 9.11 (s, 1H),8.24 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.28(d, J=7.9 Hz, 1H), 7.23-7.14 (m, 1H), 4.91-4.70 (m, 2H), 4.61-4.36 (m,2H), 3.57 (s, 3H), 2.05 (br. s., 1H), 0.94-0.69 (m, 4H). LC retentiontime 1.42 [E]. m/z: 457 (MH⁺).

The following Examples were prepared in a similar manner to Example 186:

Example Rt (min) m/z No. R¹ R² [Method] [M + H]⁺ 187

1.51 [E] 475 188

1.62 [E] 493 189

1.37 [E] 483

Example 190

Step 1

6-Chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide(prepared in Preparation 7) (25 mg, 0.078 mmol) was combined withbenzoic acid (2 mg, 0.016 mmol), L-Ascorbic acid sodium salt (2 mg,0.0010 mmol) and copper(II) sulfate (2 mg, 0.013 mmol) in a small flask.A solution of 2-azidopropane (6.65 mg, 0.078 mmol) in tert-butyl alcohol(0.5 mL) and water (0.5 mL) was subsequently added and the reaction wasstirred at room temperature for 1 hour. The reaction was diluted withdichloromethane (50 mL), washed with water (x1) and with a 1:1 mixtureof water and brine solution. The organic layer was dried over sodiumsulfate, filtered, concentrated and purified via automatedchromatography to provide6-chloro-4-((3-(1-isopropyl-1H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(24 mg, 72.0% yield). LC retention time 0.87 [J]. MS(E+) m/z: 405 (MH⁺).

Step 2

A mixture of6-chloro-4-((3-(1-isopropyl-1H-1,2,3-triazol-4-yl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(24 mg, 0.059 mmol), cyclopropanecarboxamide (10.1 mg, 0.119 mmol), andXantphos (6.9 mg, 0.012 mmol) were degassed by sparging with nitrogenfor 5 minutes. Cesium carbonate (77 mg, 0.24 mmol) and Pd₂(dba)₃ (5.4mg, 0.0059 mmol) were then added, the reaction was sealed and heated to130° C. for 60 minutes. The reaction was diluted with ethyl acetate,washed with water, saturated aqueous ammonium chloride and brine, andthen dried over sodium sulfate, filtered and concentrated. The crudeproduct was re-dissolved in DMF and purified by preparative HPLC toprovide 190 (15.4 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ 11.32 (s, 1H),10.97 (s, 1H), 9.14 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.7Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.33-7.26 (m, 1H), 4.91 (dt, J=13.5,6.7 Hz, 1H), 3.65 (s, 3H), 2.11-2.02 (m, 1H), 1.56 (d, J=6.7 Hz, 6H),0.88-0.77 (m, 4H). LC retention time 1.48 [E]. m/z: 454 (MH⁺).

Example 191

Step 1

(4-(3-((6-Chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methylpivalate (118 mg, 0.235 mmol, 79% yield) was prepared in the identicalmanner to Step 1 of Example 190, starting from6-chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine(95 mg, 0.297 mmol) and azido-methyl pivalate. LC retention time 0.98[J]. m/z: 477 (MH⁺).

Step 2

(4-(3-((6-Chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methylpivalate (22 mg, 0.046 mmol), Xantphos (5.3 mg, 0.009 mmol) and2,6-dimethylpyrimidin-4-amine (11 mg, 0.092 mmol) were combined indioxane (1.5 mL). The solution was degassed by sparging with nitrogenfor 5 minutes and then cesium carbonate (60 mg, 0.18 mmol) and Pd₂(dba)₃(4.2 mg, 0.0046 mmol) were added. The vessel was sealed and heated to125° C. for 1 hour, after which it was diluted with ethyl acetate,washed with water, saturated ammonium chloride and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated to affordthe crude product which was carried on to the final step as is. LCretention time 0.77 [J]. m/z: 564 (MH⁺).

Step 3

(4-(3-((6-((2,6-Dimethylpyrimidin-4-yl)amino)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methylpivalate (23 mg, 0.041 mmol) was dissolved in THF (0.5 mL) and sodiumhydroxide (1 M aqueous, 0.098 mL, 0.098 mmol) was added. The reactionwas stirred at room temperature for 10 minutes and then neutralized with0.11 mL of 1 M (aq.) HCl. The resultant solution was concentrated,re-dissolved in DMF, filtered and purified using preparative HPLC toprovide Example 191 (1.8 mg, 9.2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ11.05 (br. s., 2H), 10.50 (s, 1H), 9.16 (s, 1H), 8.38 (br. s., 1H),8.32-8.14 (m, 1H), 7.99-7.76 (m, 1H), 7.61 (d, J=6.7 Hz, 1H), 7.35 (t,J=7.9 Hz, 1H), 7.13 (s, 1H), 3.67 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H).LC retention time 1.16 [E]. m/z: 450 (MH⁺).

The following Examples were prepared in a similar manner to Example 191:

Example Rt (min) m/z No. R² [Method] [M + H]⁺ 192

1.12 [E] 412 193

1.17 [E] 438

Example 192 was prepared in a similar manner to Example 191.

¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.14 (s, 1H), 8.25 (s, 1H),8.14 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.29 (t,J=7.9 Hz, 1H), 3.63 (s, 3H), 2.06 (t, J=4.7 Hz, 1H), 0.90-0.69 (m, 4H).LC retention time 1.12 [E]. m/z: 412 (MH⁺).

Example 194

Step 1

To a solution of6-chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine(obtained using Preparation 7) (48 mg, 0.150 mmol) in 1,2-dichloroethane(1.5 mL) and (Z)—N-hydroxyacetimidoyl chloride (84 mg, 0.9 mmol) wasadded triethylamine (0.252 mL, 1.8 mmol). The mixture was stirredovernight at 65° C. Diluted with 50 mL dichloromethane, washed withammonium chloride and 1:1 water:brine. The organic layer was dried oversodium sulfate, filtered and concentrated. The crude product was loadedonto a 12 g silica gel column, and then purified by flashchromatography, eluting with 0-100% EtOAc in hexanes. Afforded6-chloro-4-((2-methoxy-3-(3-methylisoxazol-5-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(41 mg, 0.109 mmol, 72.5% yield) as a white solid. ¹H NMR (400 MHz,chloroform-d) δ 11.02 (s, 1H), 8.27 (br. s., 1H), 7.87 (dd, J=7.8, 1.7Hz, 1H), 7.44-7.31 (m, 2H), 7.00 (s, 1H), 6.71 (s, 1H), 3.76 (s, 3H),2.42 (s, 3H).

Step 2

6-Chloro-4-((2-methoxy-3-(3-methylisoxazol-5-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(40 mg, 0.106 mmol), Xantphos (12 mg, 0.021 mmol) andcyclopropanecarboxamide (18 mg, 0.21 mmol) were combined in dioxane (1mL). The solution was degassed by sparging with nitrogen for 5 minutesand then cesium carbonate (138 mg, 0.42 mmol) and Pd₂(dba)₃ (9.7 mg,0.011 mmol) were added. The vessel was sealed and heated to 125° C. for1 hour. The reaction was diluted with dichloromethane and thenconcentrated directly onto CELITE® and purified using automatedchromatography. The resulting material required additional purification(preparative HPLC) before providing 194 (18 mg, 38% yield). ¹H NMR (400MHz, chloroform-d) □δ 11.12 (s, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 8.17(br. s., 1H), 7.75 (dd, J=7.9, 1.5 Hz, 1H), 7.55 (dd, J=8.1, 1.5 Hz,1H), 7.35-7.30 (m, 1H), 6.70 (s, 1H), 3.78 (s, 3H), 2.40 (s, 3H),1.71-1.63 (m, 1H), 1.17-1.11 (m, 2H), 0.99-0.93 (m, 2H). LC retentiontime 0.83 [J]. m/z: 426 (MH⁺).

Step 1

A slurry of 1-(2-hydroxy-3-nitrophenyl)ethanone (1.00 g, 5.52 mmol) andpotassium carbonate (3.05 g, 22.08 mmol) in DMF (20 mL) was stirred atroom temperature for 30 min, then iodomethane (1.03 mL, 16.56 mmol) wasadded dropwise followed by stirring overnight (˜16 h) at rt. Additionaliodomethane (1.03 mL, 16.56 mmol) was added and the reaction was warmedto 50° C. for an additional 48 h. Ice cold water was added and themixture was extracted with EtOAc (80 mL×3) and the combined extractswere washed with brine, dried over sodium sulfate, filtered andconcentrated to afford 1.05 g (97%) of a tan oil as the product (notcharacterized).

Step 2

A solution of the ketone substrate (1 g, 5.12 mmol) in1,1-dimethoxy-N,N-dimethylmethanamine (12.21 g, 102 mmol) was heated to80° C. for 2 h then at reflux (120° C. oil bath temp) for an additional2 h. The reaction was cooled slightly and was concentrated on therotovap to remove the dimethyl formamide dimethyl acetal. The resultingreddish-orange oil was dissolved in toluene (˜10 mL) and re-concentratedunder vacuum and this process was repeated one additional time to ensurecomplete removal of any residual dimethyl formamide dimethyl acetal. Theresulting reddish-orange oil was then dissolved in ethanol (4 mL) andAcOH (4 mL) and cooled in an ice bath before adding hydrazine (as amonohydrate) (0.482 mL, 7.69 mmol). Let warm to room temperature thenresulting solution was heated to 80° C. for 30 minutes before coolingand concentrating on the rotovap. The resulting material was dilutedwith water (˜25 mL) which caused an oil to form from the solution. Themixture was cooled in an ice bath, sonicated, and then stirredvigorously which eventually cause the oil to solidify. After stirringvigorously overnight, the solid was collected by vacuum filtration,rinsed with water and was allowed to air dry in the funnel then undervacuum overnight to afford 1.05 g (93%) of a pale yellow solid as3-(2-methoxy-3-nitrophenyl)-1H-pyrazole. LC retention time 0.76 [J].m/z: 220 (MH⁺).

Step 3

To solution of 3-(2-methoxy-3-nitrophenyl)-1H-pyrazole (100 mg, 0.456mmol) in dichloromethane (1 mL) at room temperature was addedethoxyethene (39.5 mg, 0.547 mmol) followed by HCl (4 N in dioxane)(6.84 μl, 0.027 mmol) and the resulting clear yellow solution wasstirred at room temperature for 2 h. The mixture was then concentratedin vacuo to afford the product as a red oil. This oil was purified bydissolving into a minimum of dichloromethane and loading onto a silicagel cartridge (4 g) and eluting with a standard gradient of EtOAc inhexanes. The major UV-active product was collected near 30% EtOAc inhexanes concentration and the fractions were concentrated under vacuumto afford 104 mg (78%) of a clear pale yellow oil as the pure product.Material used as is in next reaction. LC retention time 0.96 [J]. m/z:292 (MH⁺).

Step 4

A solution of 1-(1-ethoxyethyl)-3-(2-methoxy-3-nitrophenyl)-1H-pyrazole(104 mg, 0.357 mmol) was sparged with nitrogen for a few minutes beforeadding Pd/C (38.0 mg, 0.018 mmol) followed by sparging with hydrogen gasfrom a balloon. Let stir under a balloon of hydrogen at room temperaturefor 1.5 h whereupon LCMS analysis indicated completion of the reaction.The reaction was sparged with nitrogen and the mixture was filteredthrough a Millipore filter to remove the catalyst. The resultingfiltrate was concentrated under vacuum and azeotroped with toluene thendried under vacuum overnight to afford 90 mg (96%) of a clear, paleyellow oil as the pure product. Material was used as is without anyfurther purification. LC retention time 0.67 [J]. m/z: 262 (MH⁺).

Step 5

3-(1-(1-Ethoxyethyl)-1H-pyrazol-3-yl)-2-methoxyaniline (90 mg, 0.344mmol) and 4,6-dichloro-N-d₃-methylpyridazine-3-carboxamide (68.6 mg,0.328 mmol) were dissolved in THF (2 mL) at room temperature and theresulting solution was cooled in an ice bath whereupon LiHMDS (1 M inTHF) (0.820 mL, 0.820 mmol) was added dropwise via syringe over ˜1 min.After addition was complete, the ice bath was removed and the reactionwas allowed to stir at room temperature for ˜15 min. The reaction wasquenched with a few drops of MeOH and the solution was concentrated andthe resulting oil was dissolved into a minimal amount of dichloromethane(˜1.5 mL) and was loaded onto a 4 g silica gel cartridge and eluted withEtOAc/hexanes as the eluent. Afforded 134 mg (94%) of the product as apale yellow semi-solid. Was used as is without any further purification.LC retention time 0.98 [J]. m/z: 434 (MH⁺).

Step 6

A mixture of the substrate (134 mg, 0.309 mmol), cyclopropanecarboxamide(52.6 mg, 0.618 mmol), Xantphos (35.7 mg, 0.062 mmol) and cesiumcarbonate (302 mg, 0.926 mmol) in dioxane (2 mL) was sparged withnitrogen for a few minutes before adding Pd₂(dba)₃ (56.6 mg, 0.062 mmol)and heating to reflux using a preheated 120° C. oil bath. Let continueat reflux for a total of ˜4 h. Reaction was cooled to room temperatureand partitioned between water (˜8 mL) and EtOAc (20 mL). The aqueousportion was extracted with additional EtOAc (2×10 mL) and the combinedextracts were washed with brine, dried over anhydrous sodium sulfate,decanted and concentrated under vacuum to afford a yellow stickysemi-solid as the crude product mixture. This material was dissolvedinto a minimum amount of dichloromethane (˜2 mL) and was loaded onto a 4g silica gel cartridge and was eluted with EtOAc in hexanes using astandard gradient elution. Afforded the product (112 mg, 75%) of ayellow semi-solid as the product. LC retention time 0.84 [J]. m/z: 483(MH⁺).

Example 195

To the substrate (Preparation 19, 112 mg, 0.232 mmol) was added EtOH(1.5 mL) giving a fine slurry. To this mixture at room temperature wasthen added HCl (2.5 M in EtOH) (1 mL, 2.500 mmol) giving a clear, yellowsolution. After stirring at room temperature for ˜2 h total, thesolution was concentrated under vacuum to yield a yellow oil which wasdissolved in MeOH and re-concentrated and repeating this process twomore times. Diethyl ether was added to the resulting oil and the mixturewas sonicated which caused some of the material to solidify on the sidesof the flask. Material was concentrated to yield a yellow semi-solidwhich was dried under high vacuum to yield a yellow solid. This samplewas slurried in water (˜3 mL) and saturated aqueous sodium bicarbonate(˜1 mL) was added. The resulting slurry obtained was sonicated for a fewminutes giving a fine slurry of the product which was collected byvacuum filtration followed by air drying in the funnel then slurryingthe resulting moist solid in MeOH and concentrating then dryingovernight under vacuum to afford 65 mg (67%) of a fine, pale yellowsolid as Example 195. ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (br. s., 1H),10.97 (br. s., 1H), 9.12 (br. s., 1H), 8.16 (s, 1H), 7.82 (br. s., 1H),7.72 (d, J=8.6 Hz, 1H), 7.63-7.34 (m, 2H), 7.23 (d, J=7.9 Hz, 1H), 6.75(br. s., 1H), 3.59 (s, 3H), 2.14-2.01 (m, 1H), 0.94-0.74 (m, 4H). LCretention time 0.70 [J]. m/z: 411 (MH⁺).

Example 196

Example 195 (35 mg, 0.085 mmol) and cesium carbonate (83 mg, 0.256 mmol)were mixed in DMF (0.3 mL) and 2,2-dimethyloxirane (12.30 mg, 0.171mmol) was added followed by heating the resulting mixture at 60° C. forovernight (˜16 h). The mixture was cooled, dissolved in DMSO, filteredand was purified via preparative HPLC. Unless noted (table below) themajor and minor regioisomers (assignment from unambiguous parallelsynthesis of representative examples) were isolated and characterizedseparately containing the major product were combined and dried viacentrifugal evaporation to afford 30.2 mg of Example 196. ¹H NMR (500MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.97 (s, 1H), 9.12 (s, 1H), 8.12 (s,1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.37 (d, J=7.3Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.71 (s, 1H), 4.08 (s, 2H), 2.05 (br.s., 1H), 1.09 (s, 6H), 0.89-0.72 (m, 4H). LC retention time 1.47 [E].m/z: 483 (MH⁺).

The following Examples were prepared in a similar manner to Example 196:

Example Rt (min) m/z No. R¹ R² [Method] [M + H]⁺ 197

1.79 [E] 466 198 mixture of regioisomers

1.49 [E] 463 199

1.64 [E] 434

Example 200

Example 200 was prepared in a similar manner to Example 195 by using1,1-dimethoxy-N,N-dimethylethanamine in place of1,1-dimethoxy-N,N-dimethylmethanamine in Step 3. Afforded Example 200 asa tan solid. ¹H NMR (400 MHz, methanol-d₄) δ 7.82 (dd, J=7.9, 1.5 Hz,1H), 7.69 (dd, J=8.0, 1.4 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.04 (s, 1H),6.94 (s, 1H), 3.77 (s, 3H), 2.53 (s, 3H), 1.96-1.83 (m, 1H), 1.24-1.07(m, 4H). LC retention time 0.67 [J]. m/z: 425 (MH⁺).

Example 201

Step 1

Int7 (1.14 g, 7.3 mmol) was placed in a 500 mL RBF and triethylamine(1.02 mL, 7.3 mmol) was added, followed by phosphorus oxychloride (9 mL,97 mmol). A water cooled condenser equipped with a drying tube (24/40joint size) was then attached. The flask was placed in a roomtemperature oil bath and once self-reflux ceased, the temperature wasraised to 80° C. Once that temperature was reached and the vigorousreflux subsided the temperature was raised again to 110° C. and thereaction run for 120 minutes. The heating was stopped and the reactionallowed to cool to ˜90° C. (oil bath temperature), at which point 20 mLof anhydrous 1,2-dichloroethane was added and the flask was concentratedon the rotoevaporator, first under house vac and then under oil pump.Note that the evaporated material contains POCl₃ and must be disposed ofcarefully, in this case all of the distillates were poured into arapidly stirred ethanol/ice bath. Next 20 mL of anhydrous1,2-dichloroethane was added and the mixture sonicated and thenconcentrated. Finally 30 mL of anhydrous 1,2-dichloroethane was addedand the sides of the vessel were scraped into the liqueur, the systemwas sonicated and stirred for ˜10 minutes, and concentrated. This wasslurried in 20 mL of dichloromethane. A solution of ammonium hydroxidein dichloromethane was prepared by extracting aqueous NH₄OH withdichloromethane three times. This NH₄OH solution was added gradually tothe intermediate until LCMS confirmed complete conversion. The reactionwas concentrated and then “re-dissolved” (majority of a black cruderemained adhered to sides of flask) in DCM and decanted into a cleanflask. This was absorbed onto CELITE®, dried and purified by automatedchromatography to give 4,6-dichloropyridazine-3-carboxamide (405 mg, 29%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.40-8.03 (m, 2H). LCretention time 0.45 [J]. MS(E⁺) m/z: 192 (MH⁺).

Step 2

4,6-Dichloropyridazine-3-carboxamide (160 mg, 0.833 mmol) and2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (preparationdescribed previously) (170 mg, 0.833 mmol) were dissolved in THF (2 mL).To this was added LiHMDS (1M in THF, 2.5 mL, 2.5 mmol) over c. 10minutes. After an additional 10 minutes the reaction was complete, 1 mLof 1 M HCl (aqueous) was added and then the majority of the THF wasremoved in vacuo (until a precipitate prevailed). To this was addedwater (˜50 mL) and the slurry sonicated. The slurry was filtered,rinsing with water, and then dried providing6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide(260 mg, 82%). ¹H NMR (500 MHz, chloroform-d) δ 10.71 (s, 1H), 8.13 (s,1H), 8.07 (br. s., 1H), 7.93 (dd, J=7.9, 1.7 Hz, 1H), 7.38 (dd, J=7.9,1.3 Hz, 1H), 7.30-7.27 (m, 1H), 7.01 (s, 1H), 5.64 (br. s., 1H), 4.03(d, J=0.5 Hz, 3H), 3.79 (s, 3H). LC retention time 0.68 [J]. MS(E⁺) m/z:360 (MH⁺).

Step 3

6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide(75 mg, 0.21 mmol) and cyclopropanecarboxamide (53 mg, 0.62 mmol) weredissolved in dioxane (2.6 mL). To this was added Pd₂(dba)₃ (19 mg, 0.02mmol), Xantphos (18 mg, 0.031 mmol) and cesium carbonate (136 mg, 0.42mmol). The vessel was evacuated and backfilled with nitrogen three timesand then heated to 130° C. for 90 minutes. The crude material wassuspended in hot dichloromethane and absorbed onto CELITE®, the CELITE®was dried and the material was purified by automated chromatography.Following chromatography the collected product was suspended in hotdichloromethane, cooled and then filtered, rinsing with dichloromethaneand then methanol, collecting the residual powder provided 201 (10 mg,12% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H), 11.03 (s, 1H),8.60-8.47 (m, 2H), 8.15 (s, 1H), 7.86 (s, 1H), 7.66 (dd, J=7.8, 1.4 Hz,1H), 7.51 (dd, J=7.9, 1.3 Hz, 1H), 7.27 (t, J=7.9 Hz, 1H), 3.94 (s, 3H),3.71 (s, 3H), 2.08 (quin, J=6.2 Hz, 1H), 0.89-0.75 (m, 4H). LC retentiontime 0.59 [J]. MS(E⁺) m/z: 409 (MH⁺).

Step 1

A mixture of 2-hydroxy-3-nitrobenzonitrile (500 mg, 3.05 mmol),iodomethane (0.381 mL, 6.09 mmol) and potassium carbonate (1263 mg, 9.14mmol) was stirred at room temperature for 16 hr. Additional potassiumcarbonate (1263 mg, 9.14 mmol) and iodomethane (0.381 mL, 6.09 mmol)were added and stirring was continued at room temperature for 24 hr. Thereaction was poured into ˜150 ml of water: 10% LiCl, 1:1. The resultingsuspension was filtered, the filter cake was washed with water and driedto afford 740 mg of 2-methoxy-3-nitrobenzonitrile as an off-white solid.Drying was continued under high vacuum for 7 hr to afford2-methoxy-3-nitrobenzonitrile (540 mg, 3.03 mmol, 99% yield) as an lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (dd, J=8.3, 1.7 Hz, 1H),8.18 (dd, J=7.8, 1.7 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 4.08 (s, 3H).

Step 2

A mixture of 2-methoxy-3-nitrobenzonitrile (540 mg, 3.03 mmol) and tin(II) chloride, dihydrate (2736 mg, 12.12 mmol) in EtOAc (30 mL) washeated to 80° C. for 1.5 hr. After cooling to room temperature, thereaction mixture was diluted with 30 ml of EtOAc and was washed with2.5N NaOH (3×30 ml), water (30 ml) and brine (30 ml). After drying(MgSO₄) and filtration the organic layer was concentrated to afford3-amino-2-methoxybenzonitrile (255 mg, 1.721 mmol, 56.8% yield) as anorange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.00-6.94 (m, 2H), 6.84 (dd,J=5.3, 4.0 Hz, 1H), 5.43 (s, 2H), 3.80 (s, 3H).

Step 3

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(325 mg, 1.555 mmol) and 3-amino-2-methoxybenzonitrile (255 mg, 1.721mmol) in tetrahydrofuran (14 mL) at room temperature was added dropwiseover 1 minute lithium bis(trimethylsilyl)amide (LiHMDS, 1M in THF, 3.89mL, 3.89 mmol). The resulting solution was stirred at room temperaturefor 1 hr. The reaction mixture was quenched with saturated ammoniumchloride solution (2 ml). The mixture was partitioned between EtOAc (40ml) and saturated ammonium chloride solution (40 ml). The organic layerwas washed with brine (40 ml), dried (Na₂SO₄) and concentrated to afforda solid residue that was purified on a 24 gm ISCO silica gel cartridge,eluting with a 0-100% EtOAc/hex gradient. The pure fractions wereconcentrated to afford a partially purified product that was trituratedwith ether and dried to afford6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(385 mg, 1.200 mmol, 77% yield) as an tan solid. LC retention time 2.16minutes [Q]. MS(ESI⁺) m/z: 321.2/323.3 (MH⁺), chlorine pattern. ¹H NMR(400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.39 (br. s., 1H), 7.87 (d, J=7.9Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.22 (s, 1H),3.91 (s, 3H).

Example 202

A mixture of6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(240 mg, 0.748 mmol), cyclopropanecarboxamide (127 mg, 1.496 mmol),Pd₂(dba)₃, chloroform adduct (77 mg, 0.075 mmol), Xantphos (87 mg, 0.150mmol) and Cs₂CO₃ (975 mg, 2.99 mmol) in dioxane (5 mL) was degassed bybubbling nitrogen through the mixture for 5 minutes. The reaction vesselwas sealed and heated to 130° C. for 1.5 hr. The reaction mixture wasfiltered hot (˜90° C.) through CELITE® and the filter cake was washedwith EtOAc (100 ml). The filtrate was concentrated and the residue wastriturated with MeOH. Filtration and drying afforded4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(215 mg, 0.582 mmol, 78% yield) as a tan solid. A small amount of4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideutero-methylpyridazine-3-carboxamide(20 mg, 0.054 mmol) was dissolved in DMSO. The material was furtherpurified via preparative LC/MS to afford4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(4.5 mg, 0.012 mmol, 22% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.37 (s,1H), 10.97 (s, 1H), 9.16 (s, 1H), 8.03 (s, 1H), 7.77 (d, J=7.7 Hz, 1H),7.60 (d, J=7.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 3.90 (s, 3H), 2.06 (br.s., 1H), 0.98-0.62 (m, 4H). LC retention time 1.39 minutes [E]. MS(ESI⁺)m/z: 370 (MH⁺).

Step 1

Sulfuric acid (conc. 0.53 mL, 9.9 mmol) was added to2-chloro-3-nitrobenzoic acid (2 g, 9.9 mmol) was dissolved in methylalcohol (10 mL) and the reaction heated to reflux for 12 hours. Thereaction was cooled to room temperature and then quenched with water.Ethyl acetate was added and the layers were separated, the organic layerwas washed with brine and then dried over sodium sulfate. The crudeproduct (2 g, 92% yield) was concentrated and carried on. ¹H NMR (400MHz, DMSO-d₆) δ 8.22 (dd, J=8.0, 1.6 Hz, 1H), 8.07 (dd, J=8.0, 1.6 Hz,1H), 7.72 (t, J=8.0 Hz, 1H), 3.91 (s, 3H).

Step 2

To a cooled (0° C.) solution of sodium thiomethoxide (1.50 g, 21.3 mmol)in THF (40 mL) was added methyl 2-chloro-3-nitrobenzoate (2 g, 9.3 mmol)as a solution in THF (20 mL). The reaction was stirred for 2 hours atroom temperature and then quenched with water. The product was extractedwith ethyl acetate and the combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated to providethe product (1 g, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (dd,J=8.0, 1.6 Hz, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (t, J=8.0 Hz,1H), 3.91 (s, 3H), 2.40 (s, 3H).

Step 3

To a vessel containing methyl 2-(methylthio)-3-nitrobenzoate (1 g, 4.4mmol), ammonium chloride (2.82 g, 52.8 mmol) and zinc (3.45 g, 52.8mmol) was added methanol (15 mL) and THF (5 mL). The reaction wasstirred at room temperature for 1 hour and then filtered throughCELITE®. The crude product was purified via silica gel chromatography(EtOAc: petroleum ether) to provide methyl 3-amino-2(methylthio)benzoate(500 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (dd, J=8.0, 0.8Hz, 1H), 6.84 (dd, J=8.0, 1.2 Hz, 1H), 6.61 (dd, J=7.2, 1.2 Hz, 1H),3.80 (s, 3H), 2.19 (s, 3H).

Step 4

To a solution of methyl 3-amino-2-(methylthio)benzoate (479 mg, 2.43mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (500 mg, 2.43mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (1M inTHF, 6.1 mL, 6.1 mmol). The reaction was stirred at room temperature for1 hour and then quenched with 1.5 M (aq.) HCl. The product was extractedusing ethyl acetate and the combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified via silica gel chromatography (EtOAc: petroleumether) to provide methyl3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-(methylthio)benzoate(250 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H), 9.40 (d,J=4.8 Hz, 1H), 7.30 (dd, J=8.0, 1.2 Hz, 1H), 7.53 (t, J=8.0, 1H), 7.40(dd, J=7.2, 1.2 Hz, 1H), 7.28 (s, 1H), 3.87 (s, 3H), 2.86 (d, J=4.8 Hz,3H), 2.26 (s, 3H).

Step 5

In a 10 mL pressure tube methyl3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-2-(methylthio)benzoate(250 mg, 0.68 mmol) was dissolved in dioxane (2 mL) and the vesselpurged with nitrogen for 10 minutes. Next pyridin-2-amine (128 mg, 1.36mmol), Xantphos (59 mg, 0.10 mmol), Pd₂(dba)₃ (62 mg, 0.068 mmol) andcesium carbonate (444 mg, 1.36 mmol) were added. The vessel was sealedand heated in the microwave at 120° C. for 2.5 hours. Next the reactionmixture was filtered through CELITE® eluting with ethyl acetate. Waterwas added to the ethyl acetate and the layers were separated, theaqueous layer was extracted with ethyl acetate and then the combinedorganic layers were washed with brine, dried over sodium sulfate,filtered concentrated and purified using silica gel chromatography toprovide the product (200 mg, 59% yield). LC retention time 2.15 [R].MS(E⁺) m/z: 425 (MH⁺).

Example 203

Step 1

Hydrazine hydrate (0.058 mL, 1.18 mmol) was added to a solution ofmethyl3-((3-(methylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)-2-(methylthio)benzoate(50 mg, 0.118 mmol) in ethanol (2 mL). The reaction was stirred at 100°C. for 12 hours and then concentrated to provide a crude solid. Thesolid was washed with petroleum ether and ethyl acetate to afford4-((3-(hydrazinecarbonyl)-2-(methylthio)phenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(45 mg, 81% yield). LC retention time 1.80 [R]. MS(E⁺) m/z: 425 (MH⁺).

Step 2

In a flask containing4-((3-(hydrazinecarbonyl)-2-(methylthio)phenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(45 mg, 0.106 mmol) and trifluoroacetic acid (TFA, 0.016 mL, 0.21 mmol)was added trimethyl orthoacetate (0.68 mL, 5.3 mmol). The reaction washeated to 95° C. for 30 minutes and then concentrated. The product waspurified using reverse-phase preparative HPLC to provide 203 (13 mg, 27%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (s, 1H), 10.24 (s, 1H), 9.15(d, J=4.8 Hz, 1H), 8.19 (m, 1H), 7.90 (dd, J=8.0, 1.2 Hz, 1H), 7.73 (m,2H), 7.68 (m, 2H), 6.94 (m, 1H), 2.86 (d, J=4.8 Hz, 3H), 2.61 (s, 3H),2.27 (s, 3H). LC retention time 2.03 [R]. MS(E⁺) m/z: 449 (MH⁺).

Example 204

Step 1

Methyl3-((3-(methylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)-2-(methylthio)benzoate(150 mg, 0.353 mmol) was dissolved in methanol (5 mL) and THF (5 mL) andthen lithium hydroxide (85 mg, 3.53 mmol) in water (2.5 mL) was added.The reaction was run at room temperature for 4 hours and then acidifiedto pH ˜2 using HCl. The resulting solid was collected via filtration toprovide3-((3-(methylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)-2-(methylthio)benzoicacid (110 mg, 64.5% yield). LC retention time 1.62 [R]. MS(E⁺) m/z: 411(MH⁺).

Step 2

To a solution of3-((3-(methylcarbamoyl)-6-(pyridin-2-ylamino)pyridazin-4-yl)amino)-2-(methylthio)benzoicacid (25 mg, 0.061 mmol), EDC (17.5 mg, 0.091 mmol) and HOBt (14 mg,0.091 mmol) in DMF (3 mL) was added ammonia solution (0.044 mL, 0.61mmol) and the reaction stirred for 2 hours. Water was added to thereaction and the product extracted with ethyl acetate. The organiclayers were washed with brine, dried over sodium sulfate, filtered, andpurified using silica gel chromatography to provide4-((3-carbamoyl-2-(methylthio)phenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(20 mg, 72% yield). LC retention time 1.82 [R]. MS(E⁺) m/z: 410 (MH⁺).

Step 3

A solution of4-((3-carbamoyl-2-(methylthio)phenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(25 mg, 0.061 mmol) dissolved in N,N-dimethylformamide dimethylacetal (2mL) was heated 80° C. for 3 hours. The reaction was then concentratedand taken up in acetic acid (0.5 mL) and combined with hydrazine (0.1mL, 0.061 mmol). This mixture was stirred at 95° C. for 1 hour and thenwater was added to quench the reaction. The product extracted with ethylacetate. The organic layers were washed with brine, dried over sodiumsulfate, filtered, and purified using preparative HPLC to provide 204 (8mg, 30% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 10.20 (s,1H), 9.12 (d, J=4.8 Hz, 1H), 8.26 (s, 1H), 8.19 (dd, J=8.0, 1.2 Hz, 1H),7.74 (m, 2H), 7.68 (m, 2H), 7.36 (m, 1H), 6.94 (m, 1H), 2.86 (d, J=4.8Hz, 3H), 2.18 (s, 3H). LC retention time 1.86 [R]. MS(E⁺) m/z: 434(MH⁺).

Example 205

To a solution ofN-methyl-4-((2-(methylthio)-3-(4H-1,2,4-triazol-3-yl)phenyl)amino)-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(15 mg, 0.035 mmol) in DMF (1 mL) was added potassium carbonate (14.3mg, 0.10 mmol) and then iodomethane (0.0026 mL, 0.042 mmol) in DMF (0.4mL). The reaction was run for 15 minutes at room temperature and thendiluted with water. The product extracted with ethyl acetate. Theorganic layers were washed with brine, dried over sodium sulfate,filtered, and purified using preparative HPLC to provide 205 (4 mg, 25%yield) (isolated as a single regioisomer). ¹H NMR (400 MHz, DMSO-d₆) δ11.15 (s, 1H), 10.17 (s, 1H), 9.10 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 8.19(m, 2H), 7.72 (m, 2H), 7.68 (m, 2H), 7.55 (m, 1H), 6.91 (m, 1H), 3.95(s, 3H), 2.86 (d, J=4.8 Hz, 3H), 2.21 (s, 3H). LC retention time 1.95[R]. MS(E⁺) m/z: 448 (MH⁺).

Step 1

To a suspension of 2-methoxy-3-nitrobenzamide (from Preparation 9, 500mg, 2.55 mmol) in dioxane (20 mL) was added pyridine (0.62 mL, 7.65mmol) followed by trifluoroacetic anhydride (0.72 mL, 5.1 mmol). Thereaction was run at room temperature for 3 hours and then quenched withwater. The product extracted with ethyl acetate. The organic layers werewashed with brine, dried over sodium sulfate, filtered, and purifiedusing silica gel chromatography to provide 2-methoxy-3-nitrobenzonitrile(310 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=8.0, 1.6 Hz,1H), 7.84 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 4.20 (s, 3H).

Step 2

To a vessel containing methyl 2-methoxy-3-nitrobenzonitrile (300 mg,1.684 mmol), ammonium chloride (1.08 g, 20.2 mmol) and zinc (1.32 g,20.2 mmol) was added methanol (8 mL) and THF (3 mL). The reaction wasstirred at room temperature for 1 hour and then filtered throughCELITE®. The crude product was purified via silica gel chromatography(EtOAc: petroleum ether) to provide 3-amino-2-methoxybenzonitrile (219mg, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 6.93 (m, 3H), 4.02 (s, 3H). LCretention time 1.67 [R]. MS(E⁺) m/z: 149 (MH⁺).

Step 3

To a solution of 3-amino-2-methoxybenzonitrile (180 mg, 1.213 mmol) and4,6-dichloro-N-methylpyridazine-3-carboxamide (250 mg, 1.21 mmol) in THF(6 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 3.6 mL,3.6 mmol). The reaction was stirred at room temperature for 2 hour andthen quenched with 1.5 M (aq.) HCl. The product was extracted usingethyl acetate and the combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated. The crude productwas purified via silica gel chromatography (EtOAc: petroleum ether) toprovide6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide(220 mg, 57% yield). ¹H NMR (400 MHz, CDCl₃) δ 11.04 (s, 1H), 8.26 (bs,1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (dd, J=8.0, 1.2 Hz, 1H), 7.23(t, J=8.0 Hz, 1H), 6.93 (s, 1H), 4.05 (s, 3H), 3.06 (d, J=4.2 Hz, 3H).

Step 4

In a 10 mL pressure tube6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide(200 mg, 0.629 mmol) was dissolved in dioxane (8 mL) and the vesselpurged with nitrogen for 10 minutes. Next pyridin-2-amine (71.1 mg,0.755 mmol), Xantphos (72.8 mg, 0.13 mmol), Pd₂(dba)₃ (58 mg, 0.063mmol) and cesium carbonate (410 mg, 1.26 mmol) were added. The vesselwas sealed and heated in the microwave at 110° C. for 1 hour. Next thereaction mixture was filtered through CELITE® eluting with ethylacetate. Water was added to the ethyl acetate and the layers wereseparated, the aqueous layer was extracted with ethyl acetate and thenthe combined organic layers were washed with brine, dried over sodiumsulfate, filtered concentrated and purified using silica gelchromatography to provide4-((3-cyano-2-methoxyphenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(070 mg, 29% yield). LC retention time 2.64 [R]. MS(E⁺) m/z: 376 (MH⁺).

Example 206

A solution of4-((3-cyano-2-methoxyphenyl)amino)-N-methyl-6-(pyridin-2-ylamino)pyridazine-3-carboxamide(50 mg, 0.133 mmol), hydroxylamine hydrochloride (27.8 mg, 0.400 mmol)and sodium bicarbonate (33.6 mg, 0.400 mmol) in MeOH (3 mL) was refluxedfor 6 h. Analysis of the crude mixture revealed that the startingmaterial was intact. Next 8-hydroxyquinoline (19.33 mg, 0.133 mmol) inwater (3 mL) was added and the reaction heated at 75° C. for 3 h,resulting in complete conversion to the intermediate. The reaction wasconcentrated and dissolved in dioxane and acetic anhydride (0.013 mL,0.133 mmol) was added. The reaction was heated at 90° C. for 15 hoursand then purified using preparative HPLC to provide 206 (7 mg, 12%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.18 (s, 1H), 9.12(d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.19 (m, 1H), 7.81 (dd, J=8.0, 1.2 Hz,1H), 7.68 (m, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.92(m, 1H), 3.76 (s, 3H), 2.86 (d, J=4.8 Hz, 3H), 2.69 (s, 3H). LCretention time 6.82 [P]. MS(E⁺) m/z: 433 (MH⁺).

A solution of 6-vinylpyrimidin-4-amine (prepared according to theprocedure of PCT Patent Application WO 2012/035039, Example 8, Step 2;100 mg, 0.825 mmol) in methanol (5 mL) was treated with 20% palladiumhydroxide on carbon (50 mg, 0.071 mmol). The mixture was stirred at roomtemperature under a hydrogen atmosphere for 21.25 h. The mixture wasfiltered through CELITE®, the solids were rinsed with methanol and thecombined filtrates were concentrated under vacuum to provide6-ethylpyrimidin-4-amine as a white waxy solid (94 mg, 92% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=1.1 Hz, 1H), 6.65 (br. s., 2H),6.29-6.19 (m, 1H), 2.46 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).

Step 1

A mixture of 6-chloro-2-methylpyrimidin-4-amine (300 mg, 2.09 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (386 mg, 2.51 mmol) andsodium carbonate (886 mg, 8.36 mmol) in 1,4-dioxane (9.0 mL) and water(0.9 mL) was bubbled with argon with sonication for 1 min. The mixturewas treated with tetrakis(triphenylphosphine)palladium (169 mg, 0.146mmol) and the vessel was sealed and subjected to 5 evacuate-fill cycleswith argon. The mixture was stirred on a heating block at 100° C. for16.5 h, then was cooled to room temperature, diluted with water andextracted twice with ethyl acetate. The combined organic phases werewashed with brine, dried over sodium sulfate and concentrated undervacuum. The residue was subjected to column chromatography (IscoCombiflash Companion, 24 g silica gel, 20-100% ethyl acetate-hexane, 8min, then isocratic) to provide 2-methyl-6-vinylpyrimidin-4-amine as awhite solid (189 mg, 67% yield). Mass spectrum m/z 271, (2M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 6.71 (br. s., 2H), 6.54 (dd, J=17.2, 10.6 Hz, 1H),6.26-6.20 (m, 1H), 6.20 (s, 1H), 5.53-5.40 (m, 1H), 2.31 (s, 3H).

Step 2

A solution of 2-methyl-6-vinylpyrimidin-4-amine (100 mg, 0.740 mmol) inmethanol (5 mL) was treated with 20% palladium hydroxide on carbon (50mg, 0.071 mmol). The mixture was stirred at room temperature under ahydrogen atmosphere for 15.25 h. The mixture was filtered throughCELITE® and the solids were rinsed with methanol. The filtrate wasconcentrated under vacuum to provide 6-ethyl-2-methylpyrimidin-4-amineas a white waxy solid (101 mg, quantitative yield). ¹H NMR (400 MHz,DMSO-d₆) δ 6.54 (br. s., 2H), 6.07 (s, 1H), 2.42 (q, J=7.6 Hz, 2H), 2.27(s, 3H), 1.13 (t, J=7.6 Hz, 3H).

Step 1

A mixture of (6-chloro-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (prepared according to the procedure of PCT PatentApplication WO 2012/066061, Example 24, Step 1; 250 mg, 0.727 mmol),cyclopropanecarboxamide (93 mg, 1.09 mmol), Xantphos (42 mg, 0.073 mmol)and cesium carbonate (474 mg, 1.45 mmol) in 1,4-dioxane (3 mL) wassonicated while bubbling with argon for 1 min. The mixture was treatedwith Pd₂(dba)₃ (33 mg, 0.036 mmol) and the vessel was sealed andsubjected to five evacuate-fill cycles with argon. The mixture wasstirred on a heating block at 80° C. for 16 h. The mixture was cooled toroom temperature and partitioned between water and ethyl acetate. Theaqueous phase was extracted with ethyl acetate, and the combined organicphases were washed with brine, dried over sodium sulfate andconcentrated under vacuum. The residue was subjected to columnchromatography (Isco Combiflash Companion, 40 g silica gel, 0-40% ethylacetate-hexane, 14 min, then isocratic) to provide(6-cyclopropanecarbonylamino-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester as an off-white glassy solid (182 mg, 64% yield). Massspectrum m/z 393, (M+H)⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H),8.09 (s, 1H), 2.53 (s, 3H), 1.57-1.49 (s+m, 19H), 1.20-1.11 (m, 2H),0.99-0.89 (m, 2H).

Step 2

A solution of(6-cyclopropanecarbonylamino-2-methylpyrimidin-4-yl)-bis-carbamic acidtert-butyl ester (179 mg, 0.455 mmol) in dichloromethane (2 mL) wastreated with trifluoroacetic acid (2 mL) and let stand at roomtemperature for 2.25 h. The solution was concentrated under vacuum andthe residue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic phase was dried over sodium sulfate andconcentrated under vacuum to provideN-(6-amino-2-methylpyrimidin-4-yl)cyclopropanecarboxamide as a tan solid(90 mg, quantitative yield). Mass spectrum m/z 193, (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.50 (s, 1H), 6.95 (s, 1H), 6.62 (br. s., 2H), 2.24 (s,3H), 2.04-1.90 (m, 1H), 0.79 (s, 2H), 0.77 (s, 2H).

¹H NMR (methanol-d₄ equates CDCl₃:MeOD Com- ~1:1 unless otherwise noted)Occasionally water pound suppression is used in DMSO-d₆ spectra 2 ¹H NMR(500 MHz, methanol-d₄) δ 8.30 (br. s., 1H), 8.09 (d, J = 7.9 Hz, 1H),8.00 (br. s., 1H), 7.88-7.83 (m, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.51-7.39 (m, 2H), 7.29 (d, J = 5.9 Hz, 1H), 3.13 (s, 3H) 3 ¹H NMR (500 MHz,methanol-d₄) δ 8.28 (s, 1H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 8.00 (d, J= 3.0 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.79-7.74 (m, 1H), 7.48-7.40(m, 2H), 7.28 (dd, J = 8.9, 3.5 Hz, 1H), 3.14 (s, 3H), 3.03 (s, 3H) 4 ¹HNMR (500 MHz, methanol-d₄) δ 8.24 (s, 1H), 8.09 (dd, J = 7.9, 1.5 Hz,1H), 8.00 (d, J = 3.0 Hz, 1H), 7.87-7.82 (m, 1H), 7.79-7.75 (m, 1H),7.50-7.40 (m, 2H), 7.30 (dd, J = 9.2, 3.7 Hz, 1H), 3.51 (q, J = 7.3 Hz,2H), 3.14 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H) 5 ¹H NMR (500 MHz,methanol-d₄) δ 8.22 (s, 1H), 8.10 (dd, J = 7.9, 1.0 Hz, 1H), 7.99 (d, J= 2.5 Hz, 1H), 7.86-7.80 (m, 1H), 7.79-7.72 (m, 1H), 7.48-7.40 (m, 2H),7.29 (dd, J = 8.9, 3.5 Hz, 1H), 3.14 (s, 3H), 2.94 (if, J = 7.2, 3.7 Hz,1H), 0.93-0.84 (m, 2H), 0.77-0.63 (m, 2H) 6 ¹H NMR (500 MHz, DMSO-d₆) δ11.05 (s, 1H), 10.22 (s, 1H), 9.05 (s, 1H), 8.13 (d, J = 2.8 Hz, 1H),7.98 (dd, J = 8.0, 1.4 Hz, 1H), 7.88 (s, 1H), 7.86-7.79 (m, 2H),7.72-7.63 (m, 2H), 7.45 (t, J = 6.8 Hz, 1H), 3.18 (s, 3H) 7 ¹H NMR (500MHz, methanol-d₄) δ 8.63 (s, 1H), 8.12 (dd, J = 7.9, 1.5 Hz, 1H),7.90-7.84 (m, 1H), 7.79 (td, J = 7.8, 1.2 Hz, 1H), 7.50-7.42 (m, 1H),6.83 (s, 1H), 3.14 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H) 8 N/A 9 ¹H NMR(400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 10.35 (s, 1H), 9.10 (d, J = 4.8 Hz,1H), 8.16 (d, J = 2.8 Hz, 1H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.89-7.82(m, 2H), 7.81 (s, 1H), 7.73 (m, 1H), 7.64 (dd, J = 9.2, 4.0 Hz, 1H),7.48 (m, 1H), 3.20 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H) 10 ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 10.36 (s, 1H), 9.14 (d, J = 4.4 Hz, 1H), 8.88(d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.83 (m,3H), 7.49 (m, 1H), 3.20 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.40 (s, 3H)11 ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 10.53 (s, 1H), 9.21 (d, J= 4.8 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.16 (s, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.84 (m, 2H), 7.76 (s, 1H), 7.50 (m, 1H), 7.34 (m, 1H), 3.19(s, 3H), 2.86 (d, J = 4.8 Hz, 3H) 12 ¹H NMR (400 MHz, DMSO-d₆) δ 11.38(s, 1H), 11.09 (s, 1H), 9.13 (dd, J = 9.2, 4.4 Hz, 1H), 8.09 (s, 1H),7.99 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (m, 1H), 7.71 (d, J = 7.2 Hz, 1H),7.47 (m, 1H), 3.17 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H), 2.07 (m, 1H), 0.81(m, 4H) 13 ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.16 (s, 1H),9.19 (m, 1H), 9.08 (s, 1H), 8.35 (s, 1H), 8.01 (t, J = 8.8 Hz, 2H), 7.81(m, 3H), 7.68 (m, 1H), 7.46 (m, 3H), 3.20 (s, 3H), 2.86 (d, J = 4.8 Hz,3H) 14 ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.10 (s, 1H), 9.09(dd, J = 9.6, 4.8 Hz, 1H), 8.04 (s, 1H), 7.97 (m, 2H), 7.82 (m, 2H),7.45 (m, 2H), 6.77 (dd, J = 4.8, 0.8 Hz), 3.18 (s, 3H), 2.85 (d, J = 4.8Hz, 3H), 2.27 (s, 3H) 15 N/A 16 ¹H NMR (500 MHz, methanol-d₄) δ 8.39 (s,1H), 8.14 (d, J = 4.0 Hz, 1H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 (d,J = 7.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.70-7.64 (m, 1H), 7.42 (t, J = 7.4Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.97- 6.88 (m, 1H), 3.14 (s, 3H) 17¹H NMR (500 MHz, DMSO-d₆) δ 11.39 (s, 1H), 11.10 (s, 1H), 9.12 (s, 1H),8.13-8.04 (m, 1H), 8.01-7.90 (m, 1H), 7.80-7.74 (m, 1H), 7.73- 7.67 (m,1H), 7.46 (t, J = 7.2 Hz, 1H), 3.17 (s, 3H), 2.16-1.92 (m, 1H),0.88-0.63 (m, 4H) 18 ¹H NMR (500 MHz, methanol-d₄) δ 8.10 (d, J = 5.9Hz, 1H), 8.00 (br. s., 1H), 7.95 (s, 1H), 7.76 (br. s., 2H), 7.52 (br.s., 2H), 7.06 (br. s., 1H), 3.12 (br. s., 3H), 2.31 (br. s., 3H) 19 ¹HNMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 10.41 (s, 1H), 9.11 (s, 1H),8.08-7.91 (m, 2H), 7.88-7.70 (m, 4H), 7.56-7.36 (m, 2H), 3.21 (s, 3H),2.56-2.45 (m, 3H) 20 N/A 21 N/A 22 ¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s,1H), 10.15 (br. s., 1H), 9.06 (s, 1H), 8.02-7.92 (m, 1H), 7.89-7.73 (m,4H), 7.53 (d, J = 9.4 Hz, 1H), 7.49-7.38 (m, 2H), 3.78 (s, 3H), 3.18 (s,3H) 23 ¹H NMR (500 MHz, methanol-d₄) δ 8.16-8.05 (m, 2H), 7.82-7.75 (m,1H), 7.75-7.69 (m, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.02 (s, 1H), 6.97(br. s., 1H), 3.15 (s, 3H), 2.41 (s, 3H) 24 ¹H NMR (500 MHz,methanol-d₄) δ 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H),7.74-7.66 (m, 1H), 7.61 (s, 1H), 7.42-7.33 (m, 1H), 5.86 (s, 1H), 3.60(s, 3H), 3.08 (s, 3H), 2.23 (s, 3H) 25 ¹H NMR (500 MHz, methanol-d₄) δ8.45 (br. s., 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.88-7.67 (m,2H), 7.58-7.45 (m, 4H), 7.29 (br. s., 1H), 3.16 (s, 3H) 26 ¹H NMR (500MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.65 (s, 1H), 9.15 (s, 1H), 8.52 (s,1H), 7.98 (d, J = 7.9 Hz, 1H), 7.90-7.83 (m, 2H), 7.83- 7.78 (m, 1H),7.67 (s, 1H), 7.47 (t, J = 7.6 Hz, 1H), 3.18 (s, 3H), 2.41 (s, 3H) 27 ¹HNMR (500 MHz, methanol-d₄) δ 8.48-8.42 (m, 1H), 8.19 (dd, J = 8.0, 1.4Hz, 1H), 7.97 (ddd, J = 8.5, 7.4, 1.9 Hz, 1H), 7.92-7.84 (m, 1H), 7.78(dd, J = 7.9, 1.0 Hz, 1H), 7.67 (td, J = 7.8, 1.1 Hz, 1H), 7.27 (ddd, J= 7.3, 5.3, 0.7 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.75 (s, 1H), 3.22(s, 3H) 28 ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (s, 1H), 11.12 (s, 1H),9.13 (s, 1H), 8.09 (s, 1H), 7.98 (dd, J = 7.9, 1.2 Hz, 1H), 7.82-7.76(m, 1H), 7.75- 7.70 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 5.07-4.81 (m,1H), 3.18 (s, 3H), 2.26 (dt, J = 13.7, 7.2 Hz, 1H), 1.71-1.50 (m, 1H),1.17 (ddt, J = 12.5, 9.0, 6.3 Hz, 1H) 29 ¹H NMR (500 MHz, DMSO-d₆) δ11.04 (s, 1H), 9.95 (s, 1H), 9.02 (s, 1H), 7.97 (d, J = 6.7 Hz, 1H),7.90 (s, 1H), 7.86-7.76 (m, 3H), 7.56- 7.47 (m, 1H), 7.46-7.39 (m, 2H),3.78-3.69 (m, 4H), 3.17 (s, 3H), 3.08-3.00 (m, 4H) 30 ¹H NMR (500 MHz,DMSO-d₆) δ 11.03 (s, 1H), 10.21 (s, 1H), 9.03 (br. s., 1H), 8.36 (s,1H), 7.99 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 3.7 Hz, 2H), 7.66- 7.38 (m,2H), 7.15 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 3.17 (s, 3H),2.19 (s, 3H) 31 ¹H NMR (400 MHz, DMSO-d₆)□ δ 11.06 (s, 1H), 10.20 (s,1H), 9.08 (d, J = 2.8 Hz, 1H), 8.17-8.07 (m, 2H), 7.98 (d, J = 8.4 Hz,1H), 7.88-7.78 (m, 2H), 7.72-7.64 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H),7.48-7.41 (m, 1H), 6.90 (dd, J = 6.7, 5.2 Hz, 1H), 3.18 (s, 3H), 2.85(d, J = 4.8 Hz, 3H) 32 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.07 (s, 1H), 10.67(s, 1H), 9.09 (s, 1H), 8.63 (s, 1H), 8.16 (dd, J = 8.5, 2.4 Hz, 1H),8.03 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.86-7.79 (m, 2H), 7.66 (d, J =8.5 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.17 (s, 3H) 33 ¹HNMR (500 MHz, DMSO-d₆) δ 11.06 (s, 1H), 10.36 (s, 1H), 9.12 (s, 1H),8.33 (d, J = 5.0 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.90(s, 1H), 7.81 (br. s., 2H), 7.47 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 4.4Hz, 1H), 3.17 (s, 3H), 2.58 (s, 3H) 34 ¹H NMR (500 MHz, DMSO-d₆) δ 11.03(s, 1H), 10.14 (s, 1H), 9.05 (s, 1H), 8.06-8.00 (m, 2H), 7.97 (d, J =7.9 Hz, 1H), 7.81 (d, J = 3.7 Hz, 2H), 7.56 (s, 1H), 7.45 (dt, J = 7.9,4.0 Hz, 1H), 6.84 (d, J = 4.9 Hz, 1H), 5.46 (t, J = 5.5 Hz, 1H), 4.48(d, J = 4.9 Hz, 2H), 3.16 (s, 3H) 35 ¹H NMR (500 MHz, DMSO-d₆) δ 11.06(s, 1H), 10.48 (s, 1H), 9.14 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.16 (s,1H), 7.98 (d, J = 7.3 Hz, 1H), 7.84- 7.78 (m, 2H), 7.75 (s, 1H),7.50-7.44 (m, 1H), 7.23 (d, J = 4.9 Hz, 1H), 3.17 (s, 3H) 36 ¹H NMR (500MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.65 (br. s., 1H), 9.06 (s, 1H), 8.13(d, J = 4.9 Hz, 1H), 8.00 (d, J = 7.3 Hz, 1H), 7.87-7.78 (m, 2H), 7.60(br. s., 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.29 (br. s., 1H), 6.96 (br. s.,1H), 3.20 (s, 3H), 2.63 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.3 Hz, 3H) 37¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 10.76 (br. s., 1H), 9.03 (s,1H), 8.11 (d, J = 6.1 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.87-7.76 (m,2H), 7.51 (t, J = 7.6 Hz, 1H), 7.43 (br. s., 1H), 6.91 (br. s., 1H),6.76 (br. s., 1H), 4.15 (q, J = 6.7 Hz, 2H), 3.20 (s, 3H), 1.36 (t, J =7.0 Hz, 3H) 38 ¹H NMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H), 10.88 (br. s.,1H), 9.03 (s, 1H), 8.14 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 7.3 Hz, 1H),7.86-7.76 (m, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.36 (br. s., 1H), 6.91(br. s., 1H), 6.80 (d, J = 4.9 Hz, 1H), 3.88 (s, 3H), 3.20 (s, 3H) 39 ¹HNMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.99 (s, 1H), 9.15 (s, 1H),9.07 (d, J = 1.5 Hz, 1H), 8.79 (dd, J = 2.6, 1.6 Hz, 1H), 8.65 (d, J =2.6 Hz, 1H), 8.16 (s, 1H), 7.57 (ddd, J = 7.9, 6.8, 1.5 Hz, 2H),7.45-7.28 (m, 1H), 3.51 (s, 3H), 2.16-2.02 (m, 1H), 0.87-0.76 (m, 4H) 39¹H NMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H), 10.64 (s, 1H), 9.12 (s, 1H),8.34 (d, J = 5.5 Hz, 1H), 8.29 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.85(d, J = 4.3 Hz, 2H), 7.51 (dt, J = 8.1, 4.2 Hz, 1H), 7.21 (d, J = 5.5Hz, 1H), 3.19 (s, 3H), 2.33 (s, 3H) 40 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09(s, 1H), 10.63 (s, 1H), 9.14 (s, 1H), 8.22 (br. s., 1H), 8.01 (d, J =7.9 Hz, 1H), 7.84 (d, J = 3.7 Hz, 2H), 7.50 (dt, J = 8.1, 4.2 Hz, 1H),7.34 (br. s., 1H), 4.35 (s, 2H), 3.38 (s, 3H), 3.19 (s, 3H), 2.32 (s,3H) 41 ¹H NMR (500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 10.61 (s, 1H), 9.12(s, 1H), 8.11 (br. s., 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.87-7.75 (m, 2H),7.56- 7.45 (m, 1H), 7.27 (s, 1H), 4.22 (s, 2H), 3.19 (s, 3H), 3.17 (s,3H), 2.35 (s, 3H) 42 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 10.40(s, 1H), 9.16 (s, 1H), 8.40 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.87-7.78(m, 2H), 7.74 (s, 1H), 7.48 (t, J = 7.1 Hz, 1H), 7.21 (s, 1H), 3.89 (s,3H), 3.19 (s, 3H) 43 ¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.41(s, 1H), 9.12 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.88-7.76(m, 2H), 7.56- 7.43 (m, 1H), 6.75 (s, 1H), 3.84 (s, 3H), 3.19 (s, 3H),2.30 (s, 3H) 44 ¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.38 (s,1H), 9.08 (s, 1H), 8.12 (s, 1H), 8.00 (d, J = 7.3 Hz, 1H), 7.87-7.76 (m,2H), 7.54- 7.44 (m, 1H), 6.61 (s, 1H), 5.30-5.16 (m, 1H), 3.18 (s, 3H),2.27 (s, 3H), 1.26 (d, J = 6.1 Hz, 6H) 45 ¹H NMR (500 MHz, DMSO-d₆) δ11.06 (br. s., 1H), 10.36 (br. s., 1H), 9.10 (br. s., 1H), 8.36 (s, 1H),7.99 (d, J = 7.7 Hz, 1H), 7.87-7.73 (m, 3H), 7.47 (t, J = 7.4 Hz, 1H),7.07 (s, 1H), 5.31-5.14 (m, 1H), 3.18 (s, 3H), 1.29 (d, J = 6.1 Hz, 6H)46 ¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 10.52 (s, 1H), 9.16 (s,1H), 8.57 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.88-7.79 (m,2H), 7.54 (s, 1H), 7.48 (t, J = 6.6 Hz, 1H), 3.19 (s, 3H), 2.64 (q, J =7.4 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H) 47 ¹H NMR (500 MHz, DMSO-d₆) δ11.06 (s, 1H), 10.50 (s, 1H), 9.08 (s, 1H), 8.24 (s, 1H), 8.00 (d, J =7.7 Hz, 1H), 7.82 (s, 2H), 7.58-7.42 (m, 1H), 7.09 (s, 1H), 3.17 (s,3H), 2.56 (q, J = 7.4 Hz, 2H), 2.30 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H) 48¹H NMR (500 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.08 (s, 1H), 8.19 (d, J =5.4 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.89-7.77 (m, 2H), 7.57-7.41 (m,3H), 7.07 (d, J = 5.0 Hz, 1H), 4.74 (q, J = 6.2 Hz, 1H), 3.59 (br. s.,1H), 3.21 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H) 49 ¹H NMR (500 MHz, DMSO-d₆)δ 11.05 (s, 1H), 10.19 (s, 1H), 9.05 (s, 1H), 8.10 (s, 1H), 8.05 (s,1H), 7.98 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 3.7 Hz, 2H), 7.64 (d, J =8.4 Hz, 1H), 7.51-7.43 (m, 2H), 4.41 (d, J = 5.0 Hz, 2H), 3.41 (d, J =5.4 Hz, 1H), 3.17 (s, 3H) 50 ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (s, 1H),10.13 (s, 1H), 9.07 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 5.4 Hz, 1H),7.97 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 3.4 Hz, 2H), 7.66 (s, 1H),7.48-7.41 (m, 1H), 6.97 (d, J = 5.0 Hz, 1H), 5.21 (s, 1H), 3.18 (s, 3H),1.39 (s, 6H) 51 ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.09 (s, 1H),8.19 (d, J = 5.4 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.88-7.78 (m, 2H),7.62 (br. s., 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.44 (s, 1H), 6.97 (d, J =5.0 Hz, 1H), 4.46 (s, 2H), 3.34 (s, 3H), 3.21 (s, 3H) 54 ¹H NMR (500MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.96 (s, 1H), 9.12 (s, 1H), 8.16 (s,1H), 7.77 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.37 (d, J =7.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 3.90(s, 3H), 3.58 (s, 3H), 2.12-2.02 (m, 1H), 0.89-0.74 (m, 4H) 55 ¹H NMR(500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.12 (s, 1H), 8.11 (s, 1H), 7.78(br. s., 2H), 7.68 (d, J = 7.4 Hz, 1H), 7.57 (br. s., 1H), 7.48 (d, J =7.7 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 3.61(s, 3H), 2.27 (s, 3H) 56 ¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H),10.40 (br. s., 1H), 9.12 (br. s., 1H), 8.56 (s, 1H), 8.13 (s, 1H),7.76-7.57 (m, 3H), 7.51 (br. s., 1H), 7.33 (t, J = 7.9 Hz, 1H), 3.94 (s,3H), 3.74 (s, 3H), 2.27 (s, 3H) 57 ¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s,1H), 9.10 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 8.03-7.83 (m, 2H), 7.44(t, J = 6.4 Hz, 2H), 7.31-7.16 (m, 1H), 7.09 (s, 1H), 3.89 (s, 6H), 3.16(s, 6H) 58 ¹H NMR (500 MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.84 (br. s.,1H), 9.13 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H),7.78 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.62 (br. s., 1H), 7.49 (d, J =7.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.09(t, J = 6.1 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 3.91 (s, 3H), 3.63 (s,3H) 59 ¹H NMR (500 MHz, DMSO-d₆) δ 10.93 (br. s., 1H), 10.05 (br. s.,1H), 9.08 (br. s., 1H), 8.22-8.01 (m, 1H), 7.90 (d, J = 12.8 Hz, 1H),7.62 (br. s., 1H), 7.39 (br. s., 1H), 7.23 (br. s., 1H), 3.89 (br. s.,3H), 3.16 (d, J = 4.0 Hz, 3H), 2.25 (br. s., 3H) 60 ¹H NMR (500 MHz,DMSO-d₆) δ 10.94 (s, 1H), 9.69 (br. s., 1H), 8.99 (br. s., 1H), 8.56 (s,1H), 7.81 (br. s., 1H), 7.61 (dd, J = 11.9, 8.2 Hz, 2H), 7.30 (t, J =7.7 Hz, 1H), 5.95 (br. s., 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.59 (s,3H), 2.19 (s, 3H) 61 ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.14(s, 1H), 9.07 (s, 1H), 8.26-8.07 (m, 3H), 7.92 (s, 1H), 7.69 (t, J = 7.1Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 6.7 Hz, 2H), 7.23 (t, J= 7.9 Hz, 1H), 6.97-6.85 (m, 1H), 3.89 (d, J = 2.4 Hz, 3H), 3.60 (s, 3H)62 ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.36 (s, 1H), 9.11 (s,1H), 8.57 (s, 1H), 8.29 (br. s., 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.31 (t,J = 7.7 Hz, 1H), 6.64 (br. s., 1H), 5.25 (dt, J = 12.4, 6.1 Hz, 1H),3.96 (s, 3H), 3.75 (s, 3H), 2.36 (s, 3H), 1.27 (d, J = 6.1 Hz, 6H) 63 ¹HNMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.94 (s, 1H), 9.13 (s, 1H),8.16 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.27(d, J = 7.3 Hz, 1H), 7.22-7.14 (m, 1H), 3.89 (s, 3H), 2.06 (t, J = 5.2Hz, 1H), 0.86-0.74 (m, 4H) 64 ¹H NMR (500 MHz, DMSO-d₆) δ 11.36 (s, 1H),11.04 (s, 1H), 9.16 (s, 1H), 8.25-8.14 (m, 2H), 7.78 (d, J = 1.2 Hz,1H), 7.51-7.42 (m, 2H), 7.36-7.28 (m, 1H), 6.56 (t, J = 2.1 Hz, 1H),3.45 (s, 3H), 2.08 (quin, J = 6.1 Hz, 1H), 0.87-0.76 (m, 4H) 65 ¹H NMR(500 MHz, DMSO-d₆) δ 11.17 (s, 1H), 9.14 (s, 1H), 8.30 (d, J = 4.4 Hz,1H), 8.22 (d, J = 2.0 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.79 (s, 1H),7.72 (br. s., 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H),7.46-7.35 (m, 3H), 7.09 (t, J = 6.2 Hz, 1H), 6.58 (s, 1H) 66 ¹H NMR (500MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.25 (br. s., 1H), 9.13 (s, 1H), 8.22(d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.67-7.53(m, 2H), 7.48-7.41 (m, 1H), 7.40-7.34 (m, 1H), 6.57 (s, 1H), 2.26 (s,3H) 67 ¹H NMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.94 (br. s., 2H),9.12 (s, 2H), 8.10 (s, 2H), 7.38 (d, J = 7.7 Hz, 2H), 7.24 (t, J = 7.9Hz, 2H), 2.88 (s, 3H), 2.05 (br. s., 2H), 1.89 (s, 3H), 0.90-0.74 (m,4H) 68 ¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.48 (s, 1H), 9.19(s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.65 (d, J = 7.7 Hz,2H), 7.61 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.76 (s, 3H),2.65 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H) 69 ¹H NMR (500 MHz,DMSO-d₆□□ δ 11.33 (s, 1H), 10.98 (s, 1H), 9.13 (s, 1H), 8.16 (s, 1H),7.97 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.57 (ddd, J = 18.4,7.8, 1.4 Hz, 2H), 7.44-7.30 (m, 2H), 3.47 (s, 3H), 2.69 (s, 3H),2.14-2.04 (m, 1H), 0.79-0.64 (m, 2H) 70 ¹H NMR (400 MHz, DMSO-d₆) δ11.31 (s, 1H), 10.94 (s, 1H), 9.12 (s, 1H), 8.95 (d, J = 4.8 Hz, 2H),8.15 (s, 1H), 7.58 (dd, J = 7.9, 1.5 Hz, 1H), 7.55-7.49 (m, 2H), 7.31(t, J = 7.9 Hz, 1H), 3.68 (s, 3H), 2.08 (quin, J = 6.1 Hz, 1H),0.90-0.74 (m, 4H) 71 ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 10.21(s, 1H), 9.09 (s, 1H), 8.96 (d, J = 4.8 Hz, 2H), 8.19 (s, 1H), 7.99 (s,1H), 7.74-7.65 (m, 3H), 7.58-7.45 (m, 2H), 7.42-7.33 (m, 1H), 3.70 (s,3H) 72 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.30 (s, 1H), 10.97 (s, 1H), 9.12(s, 1H), 8.77-8.65 (m, 1H), 8.17 (s, 1H), 7.91-7.86 (m, 1H), 7.86-7.82(m, 1H), 7.52 (td, J = 8.0, 1.6 Hz, 2H), 7.39 (ddd, J = 7.2, 4.9, 1.3Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 3.47 (s, 3H), 2.16-2.00 (m, 1H), 0.83(d, J = 6.1 Hz, 4H) 73 ¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.16(s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.84 (t, J= 7.4 Hz, 1H), 7.65- 7.53 (m, 2H), 7.47-7.29 (m, 3H), 7.07 (t, J = 6.1Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H) 74 ¹H NMR (400 MHz, DMSO-d₆) δ 11.01(s, 1H), 10.23 (s, 1H), 9.17- 9.06 (m, 2H), 8.83-8.76 (m, 1H), 8.66 (d,J = 2.6 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.78-7.65 (m,3H), 7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.48-7.37 (m, 1H), 3.54 (s, 3H) 75¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.99 (s, 1H), 9.15 (s, 1H),9.07 (d, J = 1.5 Hz, 1H), 8.79 (dd, J = 2.6, 1.6 Hz, 1H), 8.65 (d, J =2.6 Hz, 1H), 8.16 (s, 1H), 7.57 (ddd, J = 7.9, 6.8, 1.5 Hz, 2H),7.44-7.29 (m, 1H), 3.51 (s, 3H), 2.19-2.02 (m, 1H), 0.91-0.76 (m, 4H) 76¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.17 (s, 1H), 9.09 (s, 1H),8.57 (s, 1H), 8.28-8.13 (m, 2H), 7.77-7.53 (m, 4H), 7.32 (t, J = 7.9 Hz,1H), 6.98-6.86 (m, 1H), 3.95 (s, 3H), 3.75 (s, 3H) 77 ¹H NMR (500 MHz,DMSO-d₆) δ 10.99 (s, 1H), 10.20 (s, 1H), 9.08 (s, 1H), 8.80-8.63 (m,1H), 8.18 (d, J = 2.6 Hz, 1H), 7.99 (s, 1H), 7.93- 7.82 (m, 2H),7.75-7.67 (m, 2H), 7.62 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (dd, J = 7.8,1.5 Hz, 1H), 7.43-7.33 (m, 2H), 3.50 (s, 3H) 78 ¹H NMR (400 MHz,DMSO-d₆) δ 11.33 (s, 1H), 10.99 (s, 1H), 9.25 (dd, J = 5.0, 1.7 Hz, 1H),9.14 (s, 1H), 8.17 (s, 1H), 8.05 (dd, J = 8.6, 1.5 Hz, 1H), 7.79 (dd, J= 8.6, 5.1 Hz, 1H), 7.59 (ddd, J = 11.5, 7.9, 1.5 Hz, 2H), 7.41-7.34 (m,1H), 3.47 (s, 3H), 2.09 (quin, J = 6.2 Hz, 1H), 0.83 (d, J = 6.2 Hz, 4H)79 ¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.22 (s, 1H), 9.25 (d, J= 3.7 Hz, 1H), 9.09 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H),7.97 (s, 1H), 7.80 (dd, J = 8.4, 5.0 Hz, 1H), 7.70 (d, J = 6.1 Hz, 3H),7.55 (d, J = 7.1 Hz, 1H), 7.49-7.38 (m, 1H), 3.56-3.41 (m, 3H) 80 ¹H NMR(400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.18 (s, 1H), 9.10 (m, 1H), 8.25(s, 1H), 8.21 (m, 1H), 7.72 (m, 2H), 7.63 (m, 1H), 7.56 (d, J = 8.0 Hz,1H), 7.33 (t, J = 8.0 Hz, 1H), 7.16 (m, 1H), 6.93 (m, 1H), 3.48 (s, 3H),2.85 (d, J = 4.8 Hz, 3H), 2.65 (s, 3H), 2.29 (s, 3H) 81 ¹H NMR (400 MHz,DMSO-d₆) δ 11.01 (s, 1H), 10.18 (s, 1H), 10.49 (bs, 1H), 9.14 (m, 1H),8.23 (d, J = 4.4 Hz, 1H), 8.18 (s, 1H), 7.89 (bs, 1H), 7.78 (t, J = 3.6Hz, 1H), 7.63 (d, J = 8.0 Hz 1H), 7.56 (m, 1H), 7.49 (m, 1H), 7.33 (m,1H), 7.00 (m, 1H), 3.72 (s, 3H), 2.88 (d, J = 4.4 Hz, 3H), 2.70 (s, 3H)82 ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.92 (s, 1H), 9.12 (s,1H), 8.78 (d, J = 5.1 Hz, 1H), 8.14 (s, 1H), 7.56 (dd, J = 7.9, 1.5 Hz,1H), 7.50 (dd, J = 7.8, 1.5 Hz, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.32-7.26(m, 1H), 3.69 (s, 3H), 2.54 (s, 3H), 2.08 (quin, J = 6.1 Hz, 1H), 0.82(d, J = 5.9 Hz, 4H) 83 ¹H NMR (400 MHz, DMSO-d₆)□ δ 10.93 (s, 1H), 10.21(s, 1H), 9.09 (s, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.19 (t, J = 1.7 Hz,1H), 7.99 (s, 1H), 7.75- 7.61 (m, 3H), 7.47 (dd, J = 7.8, 1.5 Hz, 1H),7.41-7.28 (m, 2H), 3.71 (s, 3H), 2.55 (s, 3H) 84 ¹H NMR (500 MHz,DMSO-d₆)□ δ 10.98 (s, 1H), 10.10 (s, 1H), 9.11 (s, 1H), 8.55 (s, 1H),8.25-8.05 (m, 2H), 7.71-7.56 (m, 3H), 7.30 (t, J = 7.7 Hz, 1H), 6.89 (d,J = 4.7 Hz, 1H), 5.41 (d, J = 3.7 Hz, 1H), 4.67 (br. s., 1H), 3.95 (s,3H), 3.75 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H) 85 ¹H NMR (500 MHz, DMSO-d₆)δ 10.92 (s, 1H), 9.67 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H),7.77 (br. s., 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H),5.95 (br. s., 1H), 3.90 (s, 4H), 3.58 (d, J = 11.4 Hz, 6H), 2.19 (s, 3H)86 ¹H NMR (400 MHz, DMSO-d₆) δ □□.33 (s, 1H), 11.00 (s, 1H), 9.31 (d, J= 1.2 Hz, 1H), 9.15 (s, 1H), 8.89 (d, J = 5.4 Hz, 1H), 8.15 (s, 1H),7.99 (dd, J = 5.3, 1.4 Hz, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.62(dd, J = 7.9, 1.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 3.55 (s, 3H), 2.09(quin, J = 6.2 Hz, 1H), 0.87-0.77 (m, 4H) 87 ¹H NMR (500 MHz, DMSO-d₆) δ11.04 (s, 1H), 9.16 (s, 1H), 8.57 (s, 1H), 8.38 (br. s., 1H), 7.67 (d, J= 7.7 Hz, 2H), 7.45-7.23 (m, 2H), 4.36 (s, 2H), 3.95 (s, 3H), 3.75 (s,3H), 2.40 (s, 3H) 88 ¹H NMR (500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.21 (s,1H), 8.58 (s, 1H), 8.14 (br. s., 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.64 (d,J = 8.1 Hz, 1H), 7.39 (br. s., 1H), 7.33 (t, J = 7.7 Hz, 1H), 3.96 (s,3H), 3.75 (s, 3H), 2.50 (br. s., 3H), 2.45 (s, 3H), 89 ¹H NMR (500 MHz,DMSO-d₆) δ 11.01 (br. s., 1H), 10.23 (br. s., 1H), 9.31 (br. s., 1H),9.11 (br. s., 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.18 (br. s., 1H),8.04-7.91 (m, 2H), 7.76-7.61 (m, 4H), 7.43 (t, J = 7.2 Hz, 1H), 3.56 (s,3H) 90 ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.96 (s, 1H), 10.49(bs, 1H), 9.18 (m, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.61 (dd, J = 8.0,1.2 Hz, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H),3.62 (s, 3H), 2.87 (d, J = 4.8 Hz, 3H), 2.51 (s, 3H) 2.08 (m, 1H), 0.81(m, 4H) 91 ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.16 (s, 1H),9.08 (s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 8.23 (s, 1H), 8.20 (dd, J = 5.0,1.4 Hz, 1H), 7.78-7.64 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.55-7.44 (m,2H), 7.40- 7.27 (m, 1H), 6.92 (dd, J = 6.7, 5.3 Hz, 1H), 3.70 (s, 3H) 92¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.69 (s, 1H), 8.99 (s, 1H),8.95 (d, J = 4.9 Hz, 2H), 7.80 (br. s., 1H), 7.69 (dd, J = 7.9, 1.5 Hz,1H), 7.51 (t, J = 4.9 Hz, 1H), 7.48 (dd, J = 7.8, 1.5 Hz, 1H), 7.37-7.26(m, 1H), 3.69 (s, 3H), 3.59 (s, 3H), 2.20 (s, 3H) 93 ¹H NMR (500 MHz,DMSO-d₆) δ 10.94 (s, 1H), 9.68 (s, 1H), 9.00 (s, 1H), 7.95-7.72 (m, 2H),7.65 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 7.7 Hz,1H), 6.75 (d, J = 1.3 Hz, 1H), 5.96 (br. s., 1H), 3.92 (s, 4H), 3.59 (s,6H), 2.20 (s, 3H) 94 ¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.61(s, 1H), 9.18 (s, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.49 (d, J = 5.7 Hz,1H), 8.08 (s, 1H), 7.72- 7.60 (m, 3H), 7.35 (t, J = 7.9 Hz, 1H), 3.96(s, 3H), 3.75 (s, 3H) 95 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.34 (s, 1H),10.96 (s, 1H), 9.17 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H),7.51 (d, J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 3.74(s, 3H), 2.45 (s, 3H), 2.06 (d, J = 4.4 Hz, 1H), 0.85-0.77 (m, 4H) 96 ¹HNMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.18 (s, 1H), 9.31 (s, 1H),9.10 (s, 1H), 8.89 (d, J = 5.0 Hz, 1H), 8.24-8.11 (m, 2H), 8.01 (d, J =5.0 Hz, 1H), 7.79-7.63 (m, 3H), 7.56 (d, J = 8.1 Hz, 1H), 7.41 (t, J =7.9 Hz, 1H), 6.97-6.87 (m, 1H), 3.57 (s, 3H) 97 ¹H NMR (500 MHz,DMSO-d₆) δ 11.02 (s, 1H), 9.24 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.61(d, J = 7.7 Hz, 1H), 7.46-7.29 (m, 3H), 3.77 (s, 3H), 2.44 (d, J = 7.7Hz, 9H) 98 ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.36 (s, 1H),9.17 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 7.87 (s, 1H), 7.64 (t, J = 7.6Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 7.16 (s, 1H), 5.26 (dt, J = 12.2, 6.2Hz, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.30 (d, J = 6.1 Hz, 6H) 99 ¹H NMR(500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.11 (s, 1H), 8.57 (s, 1H), 8.14(br. s., 1H), 7.94 (s, 1H), 7.65 (dd, J = 14.5, 7.7 Hz, 2H), 7.36- 7.23(m, 1H), 6.62 (s, 1H), 3.95 (s, 3H), 3.80-3.70 (m, 4H), 3.31 (br. s.,1H), 3.23 (br. s., 2H), 2.33 (s, 3H) 100 ¹H NMR (500 MHz, DMSO-d₆) δ10.90 (s, 1H), 9.69 (s, 1H), 9.02 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H),7.68 (br. s., 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.40 (s, 1H), 7.35 (t, J =7.9 Hz, 1H), 5.94 (br. s., 1H), 3.75 (s, 3H), 2.45 (s, 3H), 2.17 (s, 3H)101 ¹H NMR (500 MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.92 (s, 1H), 9.16 (s,1H), 8.07 (s, 1H), 8.01 (d, J = 7.4 Hz, 1H), 7.66 (s, 1H), 7.50 (d, J =7.4 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 3.74 (s, 3H), 2.05 (t, J = 4.7Hz, 1H), 0.88-0.72 (m, 4H) 102 ¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s,1H), 9.10 (s, 1H), 8.57 (s, 1H), 8.18 (br. s., 1H), 7.90 (br. s., 1H),7.73 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 16.7, 7.9 Hz, 2H), 7.45 (d, J =8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.24- 7.00 (m, 1H), 4.45 (s, 2H),3.95 (s, 3H), 3.75 (s, 3H) 103 ¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s,1H), 9.15 (s, 1H), 8.57 (s, 1H), 8.44-8.32 (m, 2H), 7.68 (d, J = 6.4 Hz,2H), 7.33 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 5.4 Hz, 1H), 3.96 (s, 3H),3.75 (s, 3H), 2.43 (s, 3H) 104 ¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s,1H), 9.08 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J =7.7 Hz, 1H), 7.46-7.31 (m, 2H), 5.91 (s, 1H), 3.77 (s, 3H), 2.88 (s,3H), 2.72 (s, 3H), 2.18 (s, 3H) 105 ¹H NMR (500 MHz, DMSO-d₆) δ 11.34(s, 1H), 10.98 (s, 1H), 9.16 (br. s., 2H), 8.45 (s, 1H), 8.13 (s, 1H),7.67 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.34-7.24 (m, 1H),3.62 (s, 3H), 2.07 (br. s., 1H), 0.90-0.67 (m, 4H) 106 ¹H NMR (500 MHz,DMSO-d₆) δ 11.11 (s, 1H), 9.17 (d, J = 11.4 Hz, 2H), 8.47 (s, 1H), 8.14(s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 7.1 Hz, 2H), 7.45-7.32(m, 2H), 3.65 (s, 3H), 2.28 (s, 3H) 107 ¹H NMR (500 MHz, DMSO-d₆) δ11.10 (s, 1H), 9.28-8.99 (m, 2H), 8.47 (s, 1H), 7.72 (d, J = 7.7 Hz,1H), 7.58-7.43 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 5.92 (br. s., 1H),3.72-3.53 (m, 6H), 2.20 (s, 3H) 108 ¹H NMR (500 MHz, DMSO-d₆) δ 11.07(s, 1H), 9.21 (s, 1H), 8.58 (s, 1H), 8.14 (br. s., 1H), 7.70 (d, J = 7.7Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.39 (br. s., 1H), 7.33 (t, J = 7.7Hz, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 2.50 (br. s., 3H), 2.45 (s, 3H) 109¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.48 (s, 1H), 9.20 (s, 1H),8.59 (d, J = 13.8 Hz, 2H), 8.00 (s, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.60(s, 1H), 7.34 (t, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.76 (s, 3H), 2.38 (s,3H) 110 ¹H NMR (500 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.13 (s, 1H), 8.58(s, 1H), 8.29 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.61 (d, J= 7.4 Hz, 1H), 7.39-7.30 (m, 2H), 7.24 (br. s., 1H), 7.11 (d, J = 5.4Hz, 1H), 4.59 (s, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 3.52 (br. s., 1H) 111¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.78 (s, 1H), 9.01 (s, 1H),8.95 (d, J = 4.9 Hz, 2H), 7.74 (br. s., 1H), 7.69 (dd, J = 7.9, 1.5 Hz,1H), 7.56-7.44 (m, 3H), 7.40-7.28 (m, 1H), 3.72 (s, 3H), 3.69 (s, 3H)112 ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.48 (s, 1H), 9.14 (s,1H), 9.02-8.92 (m, 3H), 8.22 (dd, J = 2.6, 1.5 Hz, 1H), 8.13 (d, J = 2.7Hz, 1H), 8.01 (s, 1H), 7.69 (dd, J = 7.9, 1.5 Hz, 1H), 7.56-7.48 (m,2H), 7.43- 7.31 (m, 1H), 3.70 (s, 3H) 113 ¹H NMR (500 MHz, DMSO-d₆)□ δ10.96 (s, 1H), 10.31 (s, 1H), 9.13 (s, 1H), 8.96 (d, J = 4.9 Hz, 2H),8.91 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 0.8 Hz, 1H), 7.92 (s, 1H), 7.68(dd, J = 7.9, 1.5 Hz, 1H), 7.55-7.45 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H),3.70 (s, 3H), 2.40 (s, 3H) 114 ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (s,1H), 10.59 (s, 1H), 9.17 (s, 1H), 8.57 (s, 1H), 8.22 (br. s., 1H), 7.67(t, J = 8.2 Hz, 2H), 7.40-7.25 (m, 2H), 4.32 (s, 2H), 3.96 (s, 3H), 3.75(s, 3H), 3.26 (s, 3H), 2.36 (s, 3H) 115 ¹H NMR (500 MHz, DMSO-d₆) δ11.10 (s, 1H), 10.56 (s, 1H), 9.20 (s, 1H), 8.63 (s, 1H), 8.48 (br. s.,1H), 7.73 (dd, J = 7.7 , 3.4 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.20 (s,1H), 4.02 (s, 3H), 3.82 (s, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.46 (s, 3H),1.24 (t, J = 7.4 Hz, 3H) 116 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.31 (s, 1H),10.94 (s, 1H), 9.12 (s, 1H), 9.04 (s, 2H), 8.15 (s, 1H), 7.59 (dd, J =7.9, 1.2 Hz, 1H), 7.52 (dd, J = 7.8, 1.5 Hz, 1H), 7.31 (t, J = 7.9 Hz,1H), 3.67 (s, 3H), 2.08 (t, J = 6.0 Hz, 1H), 0.88-0.75 (m, 4H) 117 ¹HNMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 10.17 (s, 1H), 9.12 (s, 1H),8.13 (br. s., 2H), 8.00 (d, J = 7.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.65-7.50 (m, 2H), 7.36 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 5.9 Hz, 1H), 3.77(s, 3H) 118 ¹H NMR (400 MHz, DMSO-d₆)□ δ 11.00 (s, 1H), 10.59 (s, 1H),9.17 (s, 1H), 8.96 (d, J = 4.8 Hz, 2H), 8.71 (d, J = 0.9 Hz, 1H), 8.48(d, J = 5.9 Hz, 1H), 8.07 (s, 1H), 7.77-7.62 (m, 2H), 7.58-7.47 (m, 2H),7.42-7.33 (m, 1H), 3.70 (s, 3H) 119 ¹H NMR (400 MHz, DMSO-d₆) δ 10.98(s, 1H), 10.46 (s, 1H), 9.18 (s, 1H), 8.96 (d, J = 4.8 Hz, 2H), 8.59 (d,J = 0.9 Hz, 1H), 7.98 (s, 1H), 7.70 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (s,1H), 7.55-7.47 (m, 2H), 7.41-7.32 (m, 1H), 3.70 (s, 3H), 2.37 (s, 3H)120 ¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.09 (s, 1H), 9.10 (br.s., 1H), 8.56 (s, 1H), 8.22 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.72 (s,1H), 7.63 (dd, J = 17.2, 7.7 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 6.98 (d,J = 4.7 Hz, 1H), 5.22 (s, 1H), 3.95 (s, 3H), 3.75 (s, 3H), 1.40 (s, 6H)121 ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.48 (s, 1H), 9.12 (s,1H), 8.95 (d, J = 4.8 Hz, 2H), 8.37 (s, 1H), 7.73 (dd, J = 7.9, 1.3 Hz,1H), 7.58-7.47 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 3.70 (s,3H), 2.39 (s, 3H), 2.31 (s, 3H) 122 ¹H NMR (400 MHz, DMSO-d₆) δ 10.98(s, 1H), 10.35 (s, 1H), 9.12 (s, 1H), 8.96 (d, J = 5.1 Hz, 2H),7.99-7.91 (m, 2H), 7.69 (dd, J = 8.1, 1.5 Hz, 1H), 7.56-7.45 (m, 3H),7.32 (t, J = 7.9 Hz, 1H), 3.71 (s, 3H) 123 ¹H NMR (400 MHz, DMSO-d₆) δ10.99 (s, 1H), 10.46 (s, 1H), 9.14 (s, 1H), 8.96 (d, J = 4.8 Hz, 2H),8.81 (dd, J = 4.6, 1.3 Hz, 1H), 8.07-7.96 (m, 2H), 7.70 (dd, J = 7.9,1.5 Hz, 1H), 7.60 (dd, J = 9.0, 4.6 Hz, 1H), 7.55- 7.49 (m, 2H), 7.32(t, J = 7.9 Hz, 1H), 3.71 (s, 3H) 124 ¹H NMR (500 MHz, DMSO-d₆) δ 10.96(s, 1H), 9.15 (br. s., 1H), 8.11- 7.96 (m, 2H), 7.79-7.51 (m, 4H), 7.37(t, J = 7.9 Hz, 1H), 3.76 (s, 3H), 2.25 (s, 3H) 125 ¹H NMR (500 MHz,DMSO-d₆) δ 11.21 (s, 1H), 10.59 (s, 1H), 9.02 (s, 1H), 7.95 (s, 1H),7.34 (d, J = 7.7 Hz, 1H), 7.22-7.16 (m, 1H), 7.15- 7.11 (m, 1H), 6.99(t, J = 7.4 Hz, 1H), 3.79 (s, 3H), 2.11-1.89 (m, 1H), 0.88-0.70 (m, 4H)126 ¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (s, 1H), 11.00 (s, 1H), 9.25- 9.07(m, 2H), 8.24-8.11 (m, 2H), 8.01-7.87 (m, 2H), 7.45 (d, J = 7.7 Hz, 1H),7.30 (t, J = 7.9 Hz, 1H), 3.63 (s, 3H), 2.07 (d, J = 5.4 Hz, 1H),0.90-0.69 (m, 4H) 127 ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.00(s, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 5.7 Hz,1H), 7.61 (dd, J = 12.6, 7.9 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.17 (s,1H), 6.56-6.52 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 3.73 (s,3H), 1.33 (t, J = 6.9 Hz, 3H) 128 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.11 (s,1H), 9.11 (s, 1H), 8.58 (s, 1H), 8.22 (d, J = 5.4 Hz, 1H), 7.71 (d, J =7.4 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.51 (br. s., 1H), 7.33 (t, J =7.9 Hz, 1H), 7.26 (br. s., 1H), 7.02 (d, J = 4.7 Hz, 1H), 3.95 (s, 3H),3.75 (s, 3H), 2.65 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H) 129 ¹HNMR (500 MHz, DMSO-d₆)□ δ 11.06 (s, 1H), 9.22 (d, J = 1.3 Hz, 1H), 9.14(s, 1H), 8.22 (d, J = 1.3 Hz, 1H), 8.11 (s, 1H), 7.93 (d, J = 7.7 Hz,1H), 7.74 (br. s., 1H), 7.55 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.9 Hz,1H), 3.66 (s, 3H), 2.27 (s, 3H) 130 ¹H NMR (500 MHz, DMSO-d₆) δ 11.01(s, 1H), 10.48 (s, 1H), 9.20 (s, 1H), 9.12 (s, 1H), 8.36 (br. s., 1H),8.20 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.34(t, J = 7.9 Hz, 1H), 7.10 (s, 1H), 3.65 (s, 3H), 2.34 (s, 3H), 2.29 (s,3H) 131 ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.21 (s, 1H), 9.08(s, 1H), 8.21 (s, 1H), 8.02-7.87 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.36(t, J = 7.9 Hz, 1H), 5.91 (s, 1H), 3.66 (s, 3H), 2.21 (s, 4H) 132 ¹H NMR(500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.16 (s, 1H), 9.21 (s, 1H), 9.10(s, 1H), 8.26-8.13 (m, 3H), 7.90 (d, J = 7.7 Hz, 1H), 7.75- 7.66 (m,1H), 7.61-7.50 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 6.99-6.85 (m, 1H),3.65 (s, 3H) 133 ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.07 (br.s., 1H), 8.58 (s, 1H), 8.20 (d, J = 6.1 Hz, 1H), 7.71 (d, J = 7.4 Hz,1H), 7.60 (d, J = 7.7 Hz, 1H), 7.47-7.25 (m, 2H), 6.93 (br. s., 1H),6.82 (br. s., 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.75 (s, 3H) 134 ¹H NMR(500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.87 (s, 1H), 10.53 (s, 1H), 9.11(s, 1H), 8.56 (s, 1H), 8.40 (br. s., 1H), 7.94 (br. s., 1H), 7.66 (t, J= 7.9 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 3.95 (s, 3H), 3.74 (s, 3H),2.36 (s, 3H), 2.07-1.91 (m, 1H), 0.83 (d, J = 4.7 Hz, 4H) 135 ¹H NMR(500 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.13 (s, 1H), 8.57 (s, 1H), 8.26 (d,J = 5.4 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H),7.51 (br. s., 1H), 7.42-7.29 (m, 2H), 7.02 (d, J = 5.0 Hz, 1H), 4.48 (s,2H), 3.95 (s, 3H), 3.75 (s, 3H), 3.35 (s, 3H) 136 ¹H NMR (500 MHz,DMSO-d₆) δ 11.33 (s, 1H), 11.00 (s, 1H), 9.15 (s, 1H), 8.13 (d, J = 16.2Hz, 2H), 7.69 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.29 (t, J= 7.7 Hz, 1H), 4.23 (s, 3H), 3.64 (s, 3H), 2.11-2.01 (m, 1H), 0.88-0.73(m, 4H) 137 ¹H NMR (500 MHz, DMSO-d₆)□ δ 10.99 (s, 1H), 10.47 (s, 1H),9.10 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 7.4Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.08 (s,1H), 4.21 (s, 3H), 3.88 (s, 3H), 2.88 (s, 3H), 2.72 (s, 3H) 138 ¹H NMR(500 MHz, DMSO-d₆)□ δ 11.32 (s, 1H), 10.95 (s, 1H), 9.15 (s, 1H), 8.45(s, 1H), 8.11 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 7.7 Hz,1H), 7.29 (t, J = 7.9 Hz, 1H), 4.13 (s, 3H), 3.65 (s, 3H), 2.07 (d, J =5.0 Hz, 1H), 0.88-0.71 (m, 4H) 139 ¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (s,1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.09 (s, 1H), 7.48 (d, J = 7.9 Hz,1H), 7.28 (d, J = 7.3 Hz, 1H), 7.21- 7.15 (m, 1H), 3.82 (s, 3H), 2.07(br. s., 1H), 0.86-0.78 (m, 4H) 140 ¹H NMR (500 MHz, DMSO-d₆) δ 10.85(s, 1H), 10.08 (s, 1H), 9.07 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.85(s, 1H), 7.79 (s, 1H), 7.73-7.56 (m, 4H), 7.49 (t, J = 7.9 Hz, 1H), 7.36(d, J = 6.7 Hz, 1H), 2.25 (s, 3H) 141 ¹H NMR (500 MHz, DMSO-d₆) δ13.86-13.54 (m, 1H), 11.31 (br. s., 1H), 10.95 (br. s., 1H), 9.12 (br.s., 1H), 8.12 (br. s., 1H), 7.83-7.60 (m, 1H), 7.51 (d, J = 18.3 Hz,1H), 7.26 (br. s., 1H), 3.68 (br. s., 3H), 2.45- 2.25 (m, 3H), 2.10-1.98(m, 1H), 0.91-0.71 (m, 4H) 142 ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.06 (s, 1H), 9.09 (br. s., 1H), 8.06 (s, 1H), 7.97-7.85 (m, 1H),7.62 (d, J = 5.5 Hz, 2H), 7.33 (br. s., 1H), 3.69 (br. s., 3H), 2.24 (s,3H) 143 ¹H NMR (500 MHz, DMSO-d₆) δ 11.37 (s, 1H), 10.95 (s, 1H), 9.15(br. s., 1H), 8.07 (s, 1H), 7.72 (d, J = 5.7 Hz, 1H), 7.41 (br. s., 2H),7.25 (s, 1H), 7.15 (s, 1H), 7.04 (s, 1H), 3.97 (s, 3H), 2.07 (br. s.,1H), 0.91-0.69 (m, 4H) 144 ¹H NMR (500 MHz, DMSO-d₆) δ 11.06 (br. s.,1H), 9.13 (br. s., 1H), 8.37 (br. s., 1H), 7.83-7.64 (m, 2H), 7.40 (br.s., 1H), 7.11 (br. s., 1H), 4.45 (s, 3H), 3.75 (s, 3H), 2.40-2.24 (m,6H) 145 ¹H NMR (500 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.14 (s, 1H), 8.30(d, J = 4.4 Hz, 1H), 7.93-7.71 (m, 3H), 7.54-7.32 (m, 3H), 7.10-7.02 (m,1H), 3.99 (s, 3H) 146 ¹H NMR (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 11.01(s, 1H), 9.15 (s, 1H), 8.15 (s, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.63 (d,J = 7.7 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 4.45 (s, 3H), 3.73 (s, 3H),2.07 (br. s., 1H), 0.90-0.76 (m, 4H) 147 ¹H NMR (500 MHz, DMSO-d₆) δ11.03 (s, 1H), 10.18 (s, 1H), 9.10 (s, 1H), 8.33-8.11 (m, 2H), 7.77 (d,J = 8.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.41 (t, J= 7.9 Hz, 1H), 4.45 (s, 3H), 3.76 (s, 3H) 148 ¹H NMR (500 MHz, DMSO-d₆)δ 11.21 (s, 1H), 9.11 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H),7.64 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 5.93 (s, 1H), 2.90(s, 3H), 2.74 (s, 3H), 2.43 (s, 3H), 2.23 (s, 3H) 149 ¹H NMR (500 MHz,DMSO-d₆) δ 11.36 (s, 1H), 11.05 (s, 1H), 9.17 (s, 1H), 8.14 (s, 1H),7.69 (t, J = 6.4 Hz, 2H), 7.39 (t, J = 7.9 Hz, 1H), 3.76 (s, 3H), 2.60(s, 3H), 2.08 (d, J = 4.9 Hz, 1H), 0.89-0.73 (m, 4H) 150 ¹H NMR (500MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.09 (s, 1H), 9.11 (s, 1H), 8.08 (s,1H), 7.98-7.86 (m, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.70- 7.58 (m, 2H),7.49-7.38 (m, 1H), 3.77 (s, 3H), 2.60 (s, 3H), 2.25 (s, 3H) 151 ¹H NMR(500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 10.20 (s, 1H), 9.12 (s, 1H),8.26-8.14 (m, 2H), 7.83 (d, J = 7.3 Hz, 1H), 7.73-7.68 (m, 1H), 7.66 (d,J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.47-7.41 (m, 1H), 6.96- 6.90(m, 1H), 3.79 (s, 3H), 2.60 (s, 3H) 152 ¹H NMR (500 MHz, DMSO-d₆) δ11.05 (s, 1H), 9.75 (s, 1H), 9.03 (s, 1H), 7.81 (d, J = 7.7 Hz, 2H),7.64 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 5.95 (br. s., 1H),3.78 (s, 3H), 3.58 (s, 3H), 2.61 (s, 3H), 2.20 (s, 3H) 153 ¹H NMR (500MHz, DMSO-d₆)□ δ 11.10 (s, 1H), 10.53 (s, 1H), 9.16 (s, 1H), 8.37 (s,1H), 7.85 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.44 (t, J =7.9 Hz, 1H), 7.13 (s, 1H), 3.79 (s, 3H), 2.68-2.59 (m, 3H), 2.37 (s,3H), 2.31-2.13 (m, 3H) 154 ¹H NMR:400 MHz(DMSO-d₆) δ = 11.33 (s, 1 H),10.96 (s, 1 H), 9.20 (q, J = 4.7 Hz, 1 H), 8.10-8.06 (m, 2 H), 8.08 (d,J = 9.5 Hz, 2 H), 7.63 (dd, J = 1.5, 8.0 Hz, 1 H), 7.39 (t, J = 8.0 Hz,1 H), 3.74 (s, 3 H), 2.87 (d, J = 4.8 Hz, 3 H), 2.79 (s, 3 H), 2.13-2.03(m, 1 H), 0.87-0.77 (m, 4 H) 155 ¹H NMR:400 MHz(DMSO-d₆) δ = 11.04-10.99(s, 1 H), 10.53 (s, 1 H), 9.16 (q, J = 4.5 Hz, 1 H), 8.22 (d, J = 4.0Hz, 1 H), 8.12 (dd, J = 1.4, 7.9 Hz, 1 H), 7.83-7.72 (m, J = 1.4 Hz, 3H), 7.50-7.41 (m, 2 H), 7.04- 6.99 (m, J = 6.0 Hz, 1 H), 3.78 (s, 3 H),2.88 (d, J = 4.8 Hz, 3 H), 2.80 (s, 3H) 156 ¹H NMR:400 MHz(DMSO-d₆) δ =11.14-11.09 (s, 1 H), 10.54 (s, 1H), 9.14 (d, J = 4.8 Hz, 1 H), 8.26 (d,J = 4.6 Hz, 1 H), 7.85-7.76 (m, 8.0 Hz, 3 H), 7.71 (dd, J = 1.4, 7.9 Hz,1 H), 7.52-7.43 (m, 2 H), 7.02 (t, J = 6.1 Hz, 1 H), 3.80 (s, 3 H), 2.87(d, J = 4.8 Hz, 3 H), 2.61 (s, 3 H) 157 ¹H NMR (500 MHz, DMSO-d₆) δ11.13 (s, 1H), 9.23 (s, 1H), 9.15 (s, 1H), 8.33-8.18 (m, 2H), 8.00 (d, J= 7.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.46-7.28 (m, 3H), 7.10 (d, J =5.0 Hz, 1H), 4.76 (d, J = 6.4 Hz, 1H), 3.68 (s, 3H), 1.33 (d, J = 6.4Hz, 3H) 158 ¹H NMR (400 MHz, DMSO-d₆)□ δ 11.00 (s, 1H), 10.59 (s, 1H),9.13 (s, 1H), 8.96 (s, 1H), 8.95 (s, 1H), 8.42 (s, 1H), 8.35 (d, J = 5.9Hz, 1H), 7.78-7.70 (m, 1H), 7.55 (dd, J = 7.9, 1.5 Hz, 1H), 7.52 (t, J =5.0 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 5.7 Hz, 1H), 3.70(s, 3H), 2.42 (s, 3H) 159 N/A 160 ¹H NMR (500 MHz, DMSO-d₆) δ 11.34 (s,1H), 10.96 (s, 1H), 9.16 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.60 (d, J= 7.4 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.32-7.19 (m, 1H), 3.61 (s,3H), 2.68 (s, 3H), 2.17-1.96 (m, 1H), 0.93-0.69 (m, 4H) 161 ¹H NMR (500MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.70 (s, 1H), 9.02 (s, 1H), 8.16 (s, 1H),7.73 (br. s., 1H), 7.55 (dd, J = 19.0, 7.9 Hz, 2H), 7.36- 7.25 (m, 1H),5.94 (br. s., 1H), 3.63 (s, 3H), 3.56 (s, 3H), 2.69 (s, 3H), 2.18 (s,3H) 165 ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H), 10.18 (s, 1H), 9.09(s, 1H), 8.33 (d, J = 4.3 Hz, 1H), 8.23 (s, 1H), 8.19 (d, J = 3.7 Hz,1H), 7.74- 7.68 (m, 1H), 7.65 (d, J = 6.7 Hz, 1H), 7.55 (d, J = 7.9 Hz,1H), 7.29-7.24 (m, 1H), 7.23-7.19 (m, 1H), 6.96-6.89 (m, 1H), 3.72 (s,3H), 2.91-2.81 (m, 1H), 0.75-0.65 (m, 2H), 0.59-0.50 (m, 2H) 166 ¹H NMR(500 MHz, DMSO-d₆)□ δ 10.98 (s, 1H), 10.19 (s, 1H), 9.11 (s, 1H), 8.26(t, J = 5.5 Hz, 1H), 8.22 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.75- 7.65(m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 6.7 Hz, 1H), 7.32 (t, J= 7.6 Hz, 1H), 6.96-6.87 (m, 1H), 3.76 (s, 3H), 3.27 (d, J = 5.5 Hz,2H), 3.16 (d, J = 4.9 Hz, 1H), 1.15 (s, 6H) 167 ¹H NMR (500 MHz,DMSO-d₆) δ 10.96 (s, 1H), 10.18 (s, 1H), 9.09 (s, 1H), 8.30 (t, J = 5.8Hz, 1H), 8.22 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.73- 7.67 (m, 1H),7.66 (dd, J = 6.7, 2.4 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.31- 7.23 (m,2H), 6.96-6.88 (m, 1H), 3.73 (s, 3H), 3.25 (q, J = 6.7 Hz, 2H), 3.16 (d,J = 4.9 Hz, 1H), 1.56-1.46 (m, 2H), 1.37-1.18 (m, 6H), 0.90-0.82 (m, 3H)168 ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.18 (s, 1H), 9.09 (s,1H), 8.38 (t, J = 5.5 Hz, 1H), 8.24-8.16 (m, 2H), 7.73-7.64 (m, 2H),7.55 (d, J = 8.5 Hz, 1H), 7.36-7.32 (m, 1H), 7.31-7.26 (m, 1H), 6.95-6.90 (m, 1H), 3.73 (s, 3H), 3.16 (d, J = 5.5 Hz, 2H), 1.67-1.60 (m, 2H),1.14 (s, 6H) 169 ¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.33 (br.s., 1H), 9.08 (s, 1H), 8.30-8.15 (m, 2H), 8.06 (br. s., 1H), 7.81-7.70(m, 1H), 7.66 (dd, J = 7.9, 1.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H),7.35-7.31 (m, 1H), 7.31- 7.26 (m, 1H), 7.00-6.93 (m, 1H), 3.74 (s, 3H),2.80 (d, J = 4.4 Hz, 3H) 170 ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.18 (s, 1H), 9.10 (s, 1H), 8.34 (s, 1H), 8.26-8.13 (m, 2H), 7.74-7.62(m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.36-7.24 (m, 2H), 6.97-6.87 (m, 1H),4.15-4.03 (m, 2H), 3.74 (s, 3H), 3.50 (d, J = 5.5 Hz, 2H), 1.68 (t, J =6.4 Hz, 2H) 171 ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.19 (s,1H), 9.10 (s, 1H), 8.97 (t, J = 6.4 Hz, 1H), 8.24 (s, 1H), 8.19 (d, J =4.3 Hz, 1H), 7.76- 7.67 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.37-7.29 (m,2H), 6.97-6.84 (m, 1H), 4.13 (d, J = 4.9 Hz, 2H), 3.73 (s, 3H) 175 ¹HNMR (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.99 (s, 1H), 9.12 (s, 1H),8.66 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.52(d, J = 7.7 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 4.97-4.74 (m, 2H), 4.67-4.50 (m, 2H), 3.71 (s, 3H), 2.06 (d, J = 5.4 Hz, 1H), 0.92-0.66 (m, 4H)176 ¹H NMR (500 MHz, DMSO-d₆) δ (major 11.31 (s, 1H), 10.97 (s, 1H),9.11 (s, regio- 1H), 8.68 (s, 1H), 8.14 (s, 1H), 7.66 isomer (d, J = 7.7Hz, 1H), 7.53 (d, J = 7.7 only) Hz, 1H), 7.34-7.24 (m, 1H), 6.66-6.29(m, 1H), 4.82 (td, J = 15.3, 3.0 Hz, 2H), 3.70 (s, 3H), 2.14-1.96 (m,1H), 0.89-0.70 (m, 5H) 177 ¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H),10.15 (s, 1H), 9.07 (s, 1H), 8.60 (s, 1H), 8.23 (s, 1H), 8.19 (d, J =4.4 Hz, 1H), 7.75-7.60 (m, 3H), 7.56 (d, J = 8.4 Hz, 1H), 7.31 (t, J =7.9 Hz, 1H), 6.99-6.83 (m, 1H), 4.27 (q, J = 7.4 Hz, 2H), 3.74 (s, 3H),1.45 (t, J = 7.2 Hz, 3H) 178 ¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H),10.21 (s, 1H), 9.11 (s, 1H), 8.24 (s, 1H), 8.23-8.19 (m, 1H), 8.08 (s,1H), 7.79 (dd, J = 7.9, 1.2 Hz, 1H), 7.74-7.67 (m, 1H), 7.56 (d, J = 7.9Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.3, 1.2 Hz, 1H), 6.93(dd, J = 6.7, 5.5 Hz, 1H), 3.74 (s, 3H), 3.47 (s, 3H) 179 ¹H NMR (500MHz, DMSO-d₆) δ 11.36 (s, 1H), 10.96 (s, 1H), 9.15 (s, 1H), 8.08 (d, J =8.5 Hz, 2H), 7.95 (s, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.39- 7.33 (m, 1H),7.33-7.28 (m, 1H), 3.73 (s, 3H), 3.42 (s, 3H), 2.07 (br. s., 1H),0.88-0.77 (m, 4H) 180 ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.11(s, 1H), 9.11 (s, 1H), 8.09 (d, J = 17.1 Hz, 2H), 7.93 (d, J = 4.3 Hz,2H), 7.75 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 5.5 Hz, 1H), 7.41 (t, J =7.6 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 3.73 (s, 3H), 2.88 (s, 3H), 2.72(s, 3H) 183 ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (br. s., 1H), 11.05 (s,1H), 9.19 (s, 1H), 8.12 (br. s., 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.60 (d,J = 7.9 Hz, 1H), 7.39 (br. s., 1H), 7.30 (t, J = 7.9 Hz, 1H), 3.84 (s,3H), 3.73 (s, 3H), 2.45 (d, J = 6.1 Hz, 6H) 184 ¹H NMR (500 MHz,DMSO-d₆) δ 11.28 (br. s., 1H), 11.11 (s, 1H), 9.20 (s, 1H), 8.18 (br.s., 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.30 (d, J= 7.3 Hz, 1H), 3.65 (s, 3H), 3.47 (br. s., 3H), 2.51 (s, 3H), 2.43 (s,3H), 2.29 (s, 3H) 187 ¹H NMR (500 MHz, DMSO-d₆) δ 11.29 (s, 1H), 10.93(s, 1H), 9.11 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.46(d, J = 7.3 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.23-7.15 (m, 1H),6.61-6.20 (m, 1H), 4.77-4.56 (m, 2H), 3.57 (s, 3H), 2.05 (br. s., 1H),0.91-0.68 (m, 4H) 188 ¹H NMR (500 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.95(s, 1H), 9.13 (s, 1H), 8.34 (s, 1H), 8.15-8.04 (m, 2H), 7.48 (d, J = 7.3Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25-7.14 (m, 1H), 5.20 (q, J = 9.2Hz, 2H), 3.57 (s, 3H), 2.06 (t, J = 5.2 Hz, 1H), 0.87-0.69 (m, 4H) 189¹H NMR (500 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.96 (s, 1H), 9.11 (s, 1H),8.15 (s, 1H), 8.09 (d, J = 4.3 Hz, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.45(d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.22-7.16 (m, 1H), 4.06(s, 2H), 2.04 (br. s., 1H), 1.08 (s, 6H), 0.86-0.71 (m, 4H 192 ¹H NMR(500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.14 (s, 1H), 8.25 (s, 1H), 8.14 (s,1H), 7.81 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.29 (t, J =7.9 Hz, 1H), 3.63 (s, 3H), 2.06 (t, J = 4.7 Hz, 1H), 0.90-0.69 (m, 4H)193 ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.08 (br. s., 1H), 8.28(br. s., 1H), 7.86 (br. s., 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.36 (t, J =7.7 Hz, 1H), 5.92 (br. s., 1H), 3.67 (s, 3H), 3.61 (s, 3H), 2.21 (s, 3H)197 ¹H NMR (500 MHz, DMSO-d₆)□ δ 11.12 (s, 1H), 10.68 (br. s., 1H), 9.12(s, 1H), 8.28 (d, J = 4.3 Hz, 1H), 7.82 (t, J = 7.9 Hz, 2H), 7.69 (d, J= 7.9 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.37(t, J = 7.6 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 7.05 (t, J = 6.1 Hz, 1H),6.40 (d, J = 1.2 Hz, 1H), 3.70 (s, 3H), 3.41 (br. s., 3H) 198 ¹H NMR(500 MHz, DMSO-d₆) δ 11.01 (major (s, 1H), 10.48 (s, 1H), 9.12 (br.regio- s., 2H), 8.39 (br. s., 1H), 7.81-7.63 isomer (m, 2H), 7.53 (d, J= 8.1 Hz, 1H), only) 7.25 (t, J = 7.9 Hz, 1H), 7.15-7.05 (m, 1H), 6.73(s, 1H), 3.90 (s, 3H), 3.61 (s, 3H), 2.37 (s, 3H), 2.34-2.24 (m, 3H) 199¹H NMR (500 MHz, DMSO-d₆) δ 11.16 (br. s., 1H), 9.14 (br. s., 1H), 8.18(br. s., 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.52 (br. s., 1H), 7.43 (br. s.,1H), 7.37 (d, J = 8.1 Hz, 1H), 7.22 (br. s., 1H), 6.40 (br. s., 1H),3.70 (s, 3H), 3.40 (br. s., 3H), 2.29 (br. s., 3H)

SEQUENCE LISTING

This application includes a Sequence Listing submitted electronically asan ASCII text file via EFS-Web. The text file, created Nov. 18, 2019, isnamed 20191118_SEQT_12052USCNT3.txt and is 3 KB in size. The material inthe ASCII text file is hereby incorporated by reference in its entiretyherein.

What is claimed is:
 1. A method of treating psoriasis in a subject, themethod comprising orally administering to the subject a compositioncomprising a compound of the following formula:

which is6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.2. The method according to claim 1, wherein the composition is in theform of a tablet, a capsule, granules, a powder, or a liquidformulation.
 3. The method according to claim 2, wherein the compositionis in the form of a tablet.
 4. The method according to claim 2, whereinthe composition is in the form of a capsule.
 5. The method according toclaim 2, wherein the composition is in the form of granules.
 6. Themethod according to claim 2, wherein the composition is in the form of apowder.
 7. The method according to claim 2, wherein the composition isin the form of a liquid formulation.
 8. The method according to claim 7,wherein the composition is in the form of a syrup.
 9. The methodaccording to claim 1, wherein the composition is orally administered tothe subject 1 to 4 times per day.
 10. The method according to claim 9,wherein the composition is in the form of a tablet.
 11. A method oftreating psoriasis in a subject, the method comprising orallyadministering to the subject, 1 to 2 times per day, a tablet comprisinga compound of the following formula:

which is6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.12. The method according to claim 11, wherein 1 tablet per day isadministered to the subject.
 13. The method according to claim 11,wherein 2 tablets per day are administered to the subject.
 14. A methodof treating psoriasis in a subject, the method comprising orallyadministering to the subject, 1 to 2 times per day, a tablet comprisinga pharmaceutically acceptable salt of a compound of the followingformula:

which is6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.15. The method according to claim 14, wherein 1 tablet per day isadministered to the subject.
 16. The method according to claim 14,wherein 2 tablets per day are administered to the subject.